Process for the synthesis of biaryl oxazolidinones

ABSTRACT

The present invention relates to processes for the preparation of biaryl oxazolidinones. These compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.

RELATED APPLICATIONS

This application is a national stage application, filed under 35 U.S.C.§371, of International Application No. PCT/US2004/024339, filed on Jul.28, 2004, which is a continuation-in-part of U.S. patent applicationSer. No. 10/859,476, filed Jun. 2, 2004, now U.S. Pat. No. 6,969,726 andclaims the benefit of and priority to U.S. Patent Application Ser. Nos.60/490,855, filed Jul. 29, 2003; 60/529,731, filed Dec. 15, 2003, and60/531,584, filed Dec. 19, 2003, and further claims the benefit of andpriority to U.S. Patent Application Ser. Nos. 60/576,163, filed Jun. 2,2004 and 60/530,371, filed Dec. 17, 2003, the entire enclosures of whichare incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates generally to a process for synthesizinganti-infective, anti-proliferative, anti-inflammatory, and prokineticagents. More particularly, the invention relates to a process forsynthesizing biaryl oxazolidinone compounds that are useful astherapeutic agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once believed that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such beliefs have been shaken by thefact that strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. In fact, virtuallyevery antibiotic agent developed for clinical use has ultimatelyencountered problems with the emergence of resistant bacteria. Forexample, resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylococci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed, which can causeserious and even fatal results for patients infected with such resistantbacteria. Bacteria that are resistant to macrolide antibiotics, i.e.,antibiotics based on a 14- to 16-membered lactone ring, have developed.Also, resistant strains of Gram-negative bacteria such as H. influenzaeand M. catarrhalis have been identified. See, e.g., F. D. Lowry,“Antimicrobial Resistance: The Example of Staphylococcus aureus,” J.Clin. Invest., 2003, 111(9), 1265-1273; and Gold, H. S. and Moellering,R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J. Med., 1996,335, 1445-53.

The problem of resistance is not limited to the area of anti-infectiveagents, because resistance has also been encountered withanti-proliferative agents used in cancer chemotherapy. Therefore, thereexists a need for new anti-infective and anti-proliferative agents thatare both effective against resistant bacteria and resistant strains ofcancer cells.

In the antibiotic area, despite the problem of increasing antibioticresistance, no new major classes of antibiotics have been developed forclinical use since the approval in the United States in 2000 of theoxazolidinone ring-containing antibiotic,N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methylacetamide, which is known as linezolid and is sold under the tradenameZyvox® (see compound A). See, R. C. Moellering, Jr., “Linezolid: TheFirst Oxazolidinone Antimicrobial,” Annals of Internal Medicine, 2003,138(2), 135-142.

Linezolid was approved for use as an anti-bacterial agent active againstGram-positive organisms. Unfortunately, linezolid-resistant strains oforganisms are already being reported. See, Tsiodras et al., Lancet,2001, 358, 207; Gonzales et al., Lancet, 2001, 357, 1179; Zurenko etal., Proceedings Of The 39^(th) Annual Interscience Conference OnAntibacterial Agents And Chemotherapy (ICAAC); San Francisco, Calif.,USA, (Sep. 26-29, 1999). Because linezolid is both a clinicallyeffective and commercially significant anti-microbial agent,investigators have been working to develop other effective linezolidderivatives.

Notwithstanding the foregoing, there is an ongoing need for newanti-infective and anti-proliferative agents. Furthermore, because manyanti-infective and anti-proliferative agents have utility asanti-inflammatory agents and prokinetic agents, there is also an ongoingneed for new compounds useful as anti-inflammatory and prokineticagents, as well as methods for making such compounds.

SUMMARY OF THE INVENTION

The present invention provides processes for preparing biaryloxazolidinone compounds having the formula:

by combining a compound of formula (I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, whereinHet-CH₂—R³ is selected from the group consisting of:

A and B independently are selected from the group consisting of phenyl,pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; Q is a borane havingthe formula —BY² or a BF₃ alkali metal salt; Z is an electronegativesubstituent (e.g., a halogen or sulfonate); and L, M, R¹, R², R³, Y, m,and n and are defined as described below.

In another approach, the method includes the step of combining acompound of formula (III):

with a compound of formula (IV):

in a solvent in the presence of a base and a palladium catalyst, whereinA, B, Het, L, M, R¹, R², R³, Q, Z, m, and n, are defined as describedabove.

The processes of the invention can tolerate a wide variety of functionalgroups, so various substituted aryl moieties can be used. In addition,the alternate processes allow for the borane (i.e., Q) and theelectronegative substituent (i.e., Z) to be present on either arylgroup, which provides synthetic flexibility. The processes generallyprovide the desired biaryl oxazolidinone compound at or near the end ofthe overall process, and further synthetic manipulation of the biarylsystem or its substituents is generally not necessary.

The foregoing and other aspects and embodiments of the invention can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to processes for preparing biaryloxazolidinone compounds useful as anti-proliferative agents and/oranti-infective agents. The compounds may be used without limitation, forexample, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal,anti-parasitic and/or anti-viral agents. Further, compounds produced bythe processes of the invention can be used without limitation asanti-inflammatory agents, for example, for use in treating chronicinflammatory airway diseases, and/or as prokinetic agents, for example,for use in treating gastrointestinal motility disorders such asgastroesophageal reflux disease, gastroparesis (diabetic and postsurgical), irritable bowel syndrome, and constipation.

Compounds synthesized according to the methods of the invention may beused to treat a disorder in a mammal by administering to the mammal aneffective amount of one or more compounds of the invention thereby toameliorate a symptom of a particular disorder. Such a disorder can beselected from the group consisting of a skin infection, nosocomialpneumonia, post-viral pneumonia, an abdominal infection, a urinary tractinfection, bacteremia, septicemia, endocarditis, an atrio-ventricularshunt infection, a vascular access infection, meningitis, surgicalprophylaxis, a peritoneal infection, a bone infection, a jointinfection, a methicillin-resistant Staphylococcus aureus infection, avancomycin-resistant Enterococci infection, a linezolid-resistantorganism infection, and tuberculosis.

1. Definitions

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present invention.

When any variable (e.g., R¹) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹ moieties,then the group may optionally be substituted with up to two R¹ moietiesand R¹ at each occurrence is selected independently from the definitionof R¹. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present invention. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the present inventioncan be converted to N-hydroxy or N-alkoxy compounds. For example,N-hydroxy compounds can be prepared by oxidation of the parent amine byan oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl,C₃₋₁₄ carbocycle, or 3-14-membered heterocycle) derivatives.

When an atom or chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), the invention is meant to encompass each numberwithin the range as well as all intermediate ranges. For example, “C₁₋₆alkyl” is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5,1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6carbons.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon double bonds occurring at any stable point along thechain. For example, C₂₋₆ alkenyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkenyl groups. Examples of alkenyl include, but are not limitedto, ethenyl and propenyl.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon triple bonds occurring at any stable point along thechain. For example, C₂₋₆ alkynyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkynyl groups. Examples of alkynyl include, but are not limitedto, ethynyl and propynyl.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic ring” is intended to meanany stable monocyclic, bicyclic, or tricyclic ring having the specifiednumber of carbons, any of which may be saturated, unsaturated, oraromatic. For example a C₃₋₁₄ carbocycle is intended to mean a mono-,bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14carbon atoms. Examples of carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are alsoincluded in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. Preferred bridges are one ortwo carbon atoms. It is noted that a bridge always converts a monocyclicring into a tricyclic ring. When a ring is bridged, the substituentsrecited for the ring may also be present on is bridge. Fused (e.g.,naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean any stable monocyclic, bicyclic, or tricyclic ring which issaturated, unsaturated, or aromatic and comprises carbon atoms and oneor more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. A bicyclic or tricyclic heterocycle mayhave one or more heteroatoms located in one ring, or the heteroatoms maybe located in more than one ring. The nitrogen and sulfur heteroatomsmay optionally be oxidized (i.e., N→O and S(O)_(p), where p=1 or 2).When a nitrogen atom is included in the ring it is either N or NH,depending on whether or not it is attached to a double bond in the ring(i.e., a hydrogen is present if needed to maintain the tri-valency ofthe nitrogen atom). The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. Bridged rings are alsoincluded in the definition of heterocycle. A bridged ring occurs whenone or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon ornitrogen atoms. Preferred bridges include, but are not limited to, onecarbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms,and a carbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicaromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclicaromatic rings, only one of the two rings needs to be aromatic (e.g.,2,3-dihydroindole), though both may be (e.g., quinoline). The secondring can also be fused or bridged as defined above for heterocycles. Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As used herein, the term “amine protecting group” is intended to mean afunctional group that converts an amine, amide, or othernitrogen-containing moiety into a different chemical group that issubstantially inert to the conditions of a particular chemical reaction.Amine protecting groups are preferably removed easily and selectively ingood yield under conditions that do not affect other functional groupsof the molecule. Examples of amine protecting groups include, but arenot limited to, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,t-butyloxycarbonyl, p-methoxybenzyl, methoxymethyl, tosyl,trifluoroacetyl, trimethylsilyl, fluorenyl-methyloxycarbonyl,2-trimethylsilyl-ethyloxycarbonyl,1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, andbenzyloxycarbonyl. Other suitable amine protecting groups arestraightforwardly identified by those of skill in the art, e.g., byreference to Green & Wuts, Protective Groups in Organic Synthesis, 3dEd. (1999, John Wiley & Sons, Inc.).

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where processes are described as having,including, or comprising specific process steps, the processes alsoconsist essentially of, or consist of, the recited processing steps.Further, it should be understood that the order of steps or order forperforming certain actions are immaterial so long as the inventionremains operable. Moreover, two or more steps or actions may beconducted simultaneously.

2. Processes of the Invention

The processes of the invention involve a Suzuki-type coupling reactionbetween an aryl borane compound (e.g., an aryl boronic acid, arylboronic ester, aryl boronic halide, or organoborane) and an arylcompound having an electronegative substituent (e.g., an aryl halide oraryl sulfonate) in a solvent in the presence of a base and a palladiumcatalyst. See, e.g., Miyaura et al., Tetrahedron Letters, 3437 (1979),and Miyaura & Suzuki, Chem. Comm., 866 (1979).

In one aspect, the invention provides processes for synthesizingcompounds having the formula:

In one approach, the process includes the step of combining a compoundof formula (I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, wherein

A is selected from the group consisting of:

-   -   phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

B is selected from the group consisting of:

-   -   phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;

Het-CH₂—R³ is selected from the group consisting of:

M-L is selected from the group consisting of:

-   -   a) M-X, b) M-L¹, c) M-L¹-X, d) M-X-L², e) M-L¹-X-L², f)        M-X-L¹-X-L², g) M-L¹-X-L²-X, h) M-X—X—, i) M-L¹-X—X—, j)        M-X—X-L², and k) M-L¹-X—X-L², wherein        -   X, at each occurrence, independently is selected from the            group consisting of:            -   a) —O—, b) —NR⁴—, c) —N(O)—, d) —N(OR⁴)—, e)                —S(O)_(p)—, f) —SO₂NR⁴—, g) —NR⁴SO₂—, h) —NR⁴—N═, i)                ═N—NR⁴—, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n)                —NR⁴—NR⁴—, o) —NR⁴C(O)O—, p) —OC(O)NR⁴—, q)                —NR⁴C(O)NR⁴— r) —NR⁴C(NR⁴)NR⁴—, and s)

-   -   -   L¹ is selected from the group consisting of:            -   a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl, and c) C₂₋₆ alkynyl,                -   wherein any of a)-c) optionally is substituted with                    one or more R⁵ groups; and        -   L² is selected from the group consisting of:            -   a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl, and c) C₂₋₆ alkynyl,                -   wherein any of a)-c) optionally is substituted with                    one or more R⁵ groups;

alternatively, L in M-L is a bond;

M is selected from the group consisting of:

-   -   a) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, b) 3-14        membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur, c) C₁₋₆ alkyl, d)        C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, and f) —CN,        -   wherein any of a)-e) optionally is substituted with one or            more R⁵ groups;

Q is a borane having the formula —BY₂, wherein

-   -   Y, at each occurrence, independently is selected from the group        consisting of:        -   a) —OH, b) —OC₁₋₆ alkyl, c) —OC₂₋₆ alkenyl, d) —OC₂₋₆            alkynyl, e) —OC₁₋₁₄ saturated, unsaturated, or aromatic            carbocycle, f) C₁₋₆ alkyl, g) C₂₋₆ alkenyl, h) C₂₋₄ alkynyl,            and i) C₁₋₁₄ saturated, unsaturated, or aromatic carbocycle,            -   wherein any of b)-i) optionally is substituted with one                or more halogens;    -   alternatively, two Y groups taken together comprise a chemical        moiety selected from the group consisting of:        -   a) —OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—;

alternatively, Q is a BF₃ alkali metal salt or9-borabicyclo[3.3.1]nonane;

Z is selected from the group consisting of:

-   -   a) I, b) Br, c) Cl, and d) R⁹OSO₃—;

R¹, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i)        —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n)        —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)        —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v)        —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)        —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd)        —NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg)        —NR⁴C(NR⁴)NR⁴R⁴, hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴;

R², at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i)        —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n)        —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)        —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v)        —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)        —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(R⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd)        —NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg)        —NR⁴C(NR⁴)NR⁴R⁴, hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴;

R³ is selected from the group consisting of:

-   -   a) —OR⁴, b) —NR⁴R⁴, c) —C(O)R⁴, d) —C(O)OR⁴, e) —OC(O)R⁴, f)        —C(O)NR⁴R⁴, g) —NR⁴C(O)R⁴, h) —OC(O)NR⁴R⁴, i) —NR⁴C(O)OR⁴, j)        —NR⁴C(O)NR⁴R⁴, k) —C(S)R⁴, l) —C(S)OR⁴, m) —OC(S)R⁴, n)        —C(S)NR⁴R⁴, o) —NR⁴C(S)R⁴, p) —OC(S)NR⁴R⁴, q) —NR⁴C(S)OR⁴, r)        —NR⁴C(S)NR⁴R⁴, s) —C(NR⁴)R⁴, t) —C(NR⁴)OR⁴, u) —OC(NR⁴)R⁴, v)        —C(NR⁴)NR⁴R⁴, w) —NR⁴C(NR⁴)R⁴, x) —OC(NR⁴)NR⁴R⁴, y)        —NR⁴C(NR⁴)OR⁴, z) —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb)        —SO₂NR⁴R⁴, and cc) R⁴;

R⁴, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) —OR⁶, c) an amine protecting group, d) C₁₋₆ alkyl, e)        C₂₋₆ alkenyl, f) C₂₋₆ alkynyl, g) C₃₋₁₄ saturated, unsaturated,        or aromatic carbocycle, h) 3-14 membered saturated, unsaturated,        or aromatic heterocycle comprising one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, i) —C(O)—C₁₋₆ alkyl, j) —C(O)—C₂₋₆ alkenyl, k)        —C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated, unsaturated, or        aromatic carbocycle, m) —C(O)-3-14 membered saturated,        unsaturated, or aromatic heterocycle comprising one or more        heteroatoms selected from the group consisting of nitrogen,        oxygen, and sulfur, n) —C(O)O—C₁₋₆ alkyl, o) —C(O)O—C₂₋₆        alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q) —C(O)O—C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur,        -   wherein any of d)-r) optionally is substituted with one or            more R⁵ groups;

R⁵, at each occurrence, is independently selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁶, h) ═NOR⁶, i)        ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l) —CN, m) —NO₂, n) —NR⁶R⁶, o)        —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r) —C(O)NR⁶R⁶, s)        —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v) —NR⁶C(O)NR⁶R⁶, w)        —C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa)        —NR⁶C(S)R⁶, bb) —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶,        ee) —C(NR⁶)R⁶, ff) —C(NR⁶)OR⁶, gg) —OC(NR⁶)R⁶, hh)        —C(NR⁶)NR⁶R⁶, ii) —NR⁶C(NR⁶)R⁶, jj) —OC(NR⁶)NR⁶R⁶, kk)        —NR⁶C(NR⁶)OR⁶, ll) —NR⁶C(NR⁶)NR⁶R⁶, mm) —S(O)_(p)R⁶, nn)        —SO₂NR⁶R⁶, and oo) R⁶;

R⁶, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) —OR⁸, c) an amine protecting group, d) C₁₋₆ alkyl, e)        C₂₋₆ alkenyl, f) C₂₋₆ alkynyl, g) C₃₋₁₄ saturated, unsaturated,        or aromatic carbocycle, h) 3-14 membered saturated, unsaturated,        or aromatic heterocycle comprising one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, i) —C(O)—C₁₋₆ alkyl, j) —C(O)—C₂₋₆ alkenyl, k)        —C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated, unsaturated, or        aromatic carbocycle, m) —C(O)-3-14 membered saturated,        unsaturated, or aromatic heterocycle comprising one or more        heteroatoms selected from the group consisting of nitrogen,        oxygen, and sulfur, n) —C(O)O—C₁₋₆ alkyl, o) —C(O)O—C₂₋₆        alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q) —C(O)O—C₃₋₁₄ saturated,        unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered        saturated, unsaturated, or aromatic heterocycle comprising one        or more heteroatoms selected from the group consisting of        nitrogen, oxygen, and sulfur,        -   wherein any of d)-r) optionally is substituted with one or            more R⁷ groups;

R⁷, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h) ═NOR⁸, i)        ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n) —NR⁸R⁸, o)        —C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s)        —NR⁸C(O)R⁸, t) —OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w)        —C(S)R⁸, x) —C(S)OR⁸, y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa)        —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc) —NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸,        ee) —C(NR⁸)R⁸, ff) —C(NR⁸)OR⁸, gg) —OC(NR⁸)R⁸, hh)        —C(NR⁸)NR⁸R⁸, ii) —NR⁸C(NR⁸)R⁸, jj) —OC(NR⁸)NR⁸R⁸, kk)        —NR⁸C(NR⁸)OR⁸, ll) —NR⁸C(NR⁸)NR⁸R⁸, mm) —S(O)_(p)R⁸, nn)        —SO₂NR⁸R⁸, oo) C₁₋₆ alkyl, pp) C₂₋₆ alkenyl, qq) C₂₋₆ alkynyl,        rr) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and        ss) 3-14 membered saturated, unsaturated, or aromatic        heterocycle comprising one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of oo)-ss) optionally is substituted with one or            more moieties selected from the group consisting of R⁸, F,            Cl, Br, I, —CF₃, —OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸,            —C(O)OR⁸, —OC(O)R⁸, —C(O)NR⁸R⁸, —NR⁸C(O)R⁸, —OC(O)NR⁸R⁸,            —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸, —OC(S)R⁸,            —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸,            —NR⁸C(S)NR⁸R⁸, —C(NR⁸)R⁸, —C(NR⁸)OR⁸, —OC(NR⁸)R⁸,            —C(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)R⁸, —OC(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)OR⁸,            —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸, and —S(O)_(p)R⁸;

R⁸, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) H, b) an amine protecting group, c) C₁₋₆ alkyl, d) C₂₋₆        alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated, unsaturated, or        aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or        aromatic heterocycle comprising one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur, h)        —C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆        alkynyl, k) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic        carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or        aromatic heterocycle comprising one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur, m)        —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆        alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic        carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated,        or aromatic heterocycle comprising one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur,        -   wherein any of c)-q) optionally is substituted with one or            more moieties selected from the group consisting of F, Cl,            Br, I, —CF₃, —OH, —OC₁₋₆ alkyl, —SH, —SC₁₋₆ alkyl, —CN,            —NO₂, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)C₁₋₆ alkyl,            —C(O)OC₁₋₆ alkyl, —C(O)NH₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆            alkyl)₂, —NHC(O)C₁₋₆ alkyl, —SO₂NH₂—, —SO₂NHC₁₋₆ alkyl,            —SO₂N(C₁₋₆ alkyl)₂, and —S(O)_(p)C₁₋₆ alkyl;

R⁹ is selected from the group consisting of:

-   -   a) C₁₋₆ alkyl, b) phenyl, and c) toluoyl;        -   wherein any of a)-c) optionally is substituted with one or            more moieties selected from the group consisting of F, Cl,            Br, and I;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p, at each occurrence, independently is 0, 1, or 2.

In an alternative approach, the method includes the step of combining acompound of formula (III):

with a compound of formula (IV):

in a solvent in the presence of a base and a palladium catalyst, whereinA, B, Het, L, M, R¹, R², R³, R⁴, Q, Z, m, and n are defined as describedabove.

In another aspect, the invention provides processes for preparing acompound having the formula:

In one approach, the process includes the step of combining a compoundof formula (V):

with a compound of formula (VI):

in a solvent in the presence of a base and a palladium catalyst. In analternative approach, the method includes the step of combining acompound of formula (VII):

with a compound of formula (VIII):

in a solvent in the presence of a base and a palladium catalyst. Ineither approach, A, B, L, M, R¹, R², R³, Q, Z, m, and n are defined asdescribed above.

In yet another aspect, the invention provides processes for preparing acompound having the formula:

In one approach, the process includes the step of combining a compoundof formula (IX):

with a compound of formula (X):

in a solvent in the presence of a base and a palladium catalyst.Alternatively, the compound can be prepared by combining a compound offormula (XI):

with a compound of formula (XII):

in a solvent in the presence of a base and a palladium catalyst. Ineither approach, A, B, L, M, R¹, R², R³, Q, Z, m, and n are defined asdescribed above.

Embodiments of any of the above processes can include the following:

In preferred compounds, A and B independently are selected from thegroup consisting of phenyl and pyridyl, and m and n independently are 0,1, or 2. R³ can be triazole, tetrazole, oxazole, or isoxazole, andparticularly [1,2,3]triazol-1-yl. Alternatively, R³ can be —NHC(O)R⁴,and particularly —NHC(O)CH₃.

In various embodiments, compounds (II), (VI), or (X) can have a formulaselected from:

wherein R², R³, Z, and n are defined as described above.

In addition, compounds (I), (V), or (IX) can have a formula selectedfrom:

wherein L, M, Q, R¹, and m are defined as described above.

In other embodiments, compounds (IV), (VIII), or (XII) can have aformula selected from:

wherein R², R³, Q, and n are defined as described above.

Additionally, compounds (III), (VII), or (XI) can have one of thefollowing formulas:

wherein L, M, R¹, Z, and m are defined as described above.

In any of these embodiments, M-L can be M-CH₂—X—CH₂—. In someembodiments, X is —NR⁴—, where R⁴ can be, for example, H or an amineprotecting group. Examples of suitable amine protecting groups includebenzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarbonyl,p-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsilyl,fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyloxycarbonyl,1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, andbenzyloxycarbonyl. In embodiments where R⁴ is an amine protecting group,the processes can include the step of removing the amine protectinggroup.

In alternative embodiments, M-L is M-S-L¹-NR⁴-L², wherein L¹ and L² areC₁₋₆ alkyl. Particularly, M-L can be M-S—CH₂CH₂—NH—CH₂—. In still otherembodiments, L is C₁₋₆ alkyl, and particularly —CH₂—.

In the above embodiments, M can be a 5-6 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur.Examples of suitable heterocycles include triazole, tetrazole, oxazole,and isoxazole, and particularly isoxazol-4-yl, [1,2,3]triazol-1-yl, and[1,2,3]triazol-4-yl.

Alternatively, M-L can be M-X—CH₂—. In some embodiments, X is —NR⁴—,where R⁴ can be, for example, H or an amine protecting group, asdescribed above. In embodiments where R⁴ is an amine protecting group,the processes can include the step of removing the amine protectinggroup. In other embodiments, M-L is

or, more particularly,

In the above embodiments, M can be a halogenated C₁₋₆ alkyl, C₂₋₆alkenyl, or C₂₋₆ alkynyl group, optionally substituted with one or moreR⁵ groups, as defined above. Alternatively, M can be a —CN group. Inparticular embodiments, M is a C₁₋₆ alkyl substituted with one or moreatoms selected from the group consisting of F, Cl, Br, and I, forexample, —CH₂CH₂CH₂F. M can also be a C₁₋₆ alkyl substituted with one ormore —CN groups, for example, —CH₂CH₂CN. Other examples of suitable Mgroups include, but are not limited to, —CH₂CH(OH)CH₂F and —CH₂C(O)NH₂.

In alternative embodiments, M is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl, wherein one or more carbons is replaced with S(O)_(p) and oneor more of the remaining carbons optionally is substituted with one ormore R⁵ groups.

Other embodiments include compounds wherein M has the formula:

wherein V is H, —NR⁴R⁴, —OR⁴, or C₁₋₆ alkyl optionally substituted withone or more R⁵ groups; W is O or S; and L¹ and L² are defined asdescribed above.

The Z group can be a halogen or a sulfonate. Examples of suitablesulfonates include, but are not limited to, methanesulfonate(“mesylate”), trifluoromethanesulfonate (“triflate”), andp-toluenesulfonate (“tosylate”). In preferred embodiments, the Z groupis I. Preferred Q groups include —B(OH)₂, —BF₂.KF, and

In any of the above processes, the base can be selected from the groupconsisting of alkali metal hydroxides, alkali metal carbonates, alkalimetal fluorides, trialkyl amines, and mixtures thereof. Examples ofsuitable bases include potassium carbonate, sodium carbonate, sodiummethoxide, sodium ethoxide, potassium fluoride, triethylamine,diisopropylethylamine, and mixtures thereof. In certain embodiments, theratio of equivalents of base to equivalents of compound (I), (IV), (V),(VIII), (IX), or (XII) is about 3:1.

The catalyst can be a palladium catalyst, for example, a ligandcoordinated palladium(0) catalyst (e.g., atetrakis(trialkylphosphine)palladium(0) or a tetrakis(triarylphosphine)palladium(0) catalyst) or a ligand coordinated palladium(II) catalyst.Suitable catalysts include, for example,tetrakis(triphenylphosphine)palladium(0),dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, andpalladium(II) chloride. In particular embodiments, the catalyst istetrakis(triphenylphosphine) palladium(0), and the ratio of theequivalents of the catalyst to the equivalents of compound (I), (IV),(V), (VIII), (IX), or (XII) is about 1:20.

The solvent can be an aqueous solvent, or a mixture of water and anorganic solvent, wherein the organic solvent is selected from the groupconsisting of methanol, ethanol, propanol, isopropanol, butanol,isobutanol, secondary butanol, tertiary butanol, benzene, toluene,tetrahydrofuran, dimethylformamide, 1,2-diethyl ether, dimethoxyethane,diisopropyl ether, methyltertiarybutyl ether, methoxymethyl ether,2-methoxyethyl ether, 1,4-dioxane, 1,3-dioxolane, and mixtures thereof.In particular embodiments, the solvent is a mixture of water, toluene,and ethanol, for example, in a ratio of about 1:3:1 by volume.

The process can be carried out at a temperature of about 20° C. to about100° C. In some embodiments, the process is carried out at the refluxtemperature of the solvent.

Other reaction conditions for the Suzuki-type coupling reactions of theinvention are straightforwardly identified by those of skill in the art,e.g., by reference to Suzuki & Brown, Organic Synthesis Via BoranesVolume 3: Suzuki Coupling, (Aldrich, 2003).

Table 1 includes exemplary compounds that can be synthesized accordingto the processes of the invention.

TABLE 1 Compound Number Structure 1

(5S)N-[3-(2-Fluoro-4′-{[(quinolin-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 2

(5S)N-[3-(2-Fluoro-4′-{[([1,2,3]thiadiazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 3

(5S)N-{3-[3-Fluoro-4-(6-tetrazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4

(5S)N-[3-(2-Fluoro-4′-[1,2,3]triazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 5

(5S)N-[3-(2-Fluoro-4′-{[(isoxazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 6

(5S)N-[3-(2-Fluoro-4′-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 7

(5R)3-(2-Fluoro-4′-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 8

(5S)N-[3-(2-Fluoro-4′-{[methyl-(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 9

(5S)N-[3-(2-Fluoro-4′-pyrrolidin-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 10

(5S)N-[3-(2-Fluoro-4′-piperidin-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 11

(5S)N-(3-{2-Fluoro-4′-[(3-fluoro-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 12

(5S)N-(3-{4′-[(2-Cyano-ethylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 13

(5S)N-{3-[4-(4-N-(N-methyl-N′-cyano) guanylaminomethyl-phenyl-4-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 14

(5R)2-{[2′-Fluoro-4′-(2-oxo-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-3-yl)-biphenyl-4-ylmethyl]-amino}-acetamide 15

(5S)N-(3-{2-Fluoro-4′-[(3-fluoro-2-hydroxy-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 16

(5R)3-{2-Fluoro-4′-[(3-fluoro-propylamino)-methyl]biphenyl-4-yl}-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 17

(5S)N-{3-[4′-(Ethanesulfonylamino-methyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 18

(5S)N-[3-(2-Fluoro-4′-methylsulfamoylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 19

(5S)N-(3-{2-Fluoro-4′-[3-(3-imidazol-1-yl-propyl)-ureido]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 20

(5S)N-[3-(2-Fluoro-4′-{[2-(3H-[1,2,3]triazol-4-ylsulfanyl)-ethylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 21

(5S)N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfonyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 22

(5S)N-(3-{2-Fluoro-4′-[(pyridin-2-ylmethyl)-sulfamoyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 23

(5S)N-(3-{2-Fluoro-4′-[(1-methyl-1H-imidazole-4-sulfonylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 24

(5S)N-{3-[2-Fluoro-4′-([1,2,4]triazol-4-ylaminomethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 25

(5S)N-{3-[2-Fluoro-4′-(3H-[1,2,3]triazole-4-sulfonylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 26

(5S)2-({4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-amino)-acetamide 27

(5S)N-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-2-amino-acetamide 28

(5S)N-{3-[2-Fluoro-4′-(methanesulfonylamino-methyl)-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl}-acetamide 29

(5S)N-{3-[2,3′-Difluoro-4′-(methanesulfonylamino-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 30

(5S)N-[3-(2-Fluoro-4′-tetrazol-2-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 31

(5S)N-{3-[2-Fluoro-4′-(pyridin-4-ylmethanesulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 32

(5S)N-{3-[3-Fluoro-4-(6-tetrazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 33

(5S)N-{3-[3-Fluoro-4-(6-[1,2,3]triazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 34

(5S)N-{3-[2-Fluoro-4′([1,3,4]thiadiazole-2-sulfinylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 35

(5S)N-[3-(2-F1uoro-4′-[1,2,4]triazol-1-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 36

(5S)N-{3-[2-Fluoro-4′-(5-methyl-tetrazol-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 37

(5S)N-{3-[2-Fluoro-4′-(5-methyl-tetrazol-2-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 38

(S,S)N-{3-[2-Fluoro-4′-(1-hydroxy-2-[1,2,3]triazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 39

(5S)N-(3-{2-Fluoro-4′-[(2-methylsulfanyl-ethylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 40

(5S)N-{3-[3-Fluoro-4-(6-[1,2,4]triazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 41

(5S)N-(3-{4′-[(Acetyl-cyanomethyl-amino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 42

(5S)N-{3-[3-Fluoro-4-(6-pyrazol-1-ylmethyl-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 43

(5S)N-{3-[4′-(5-Chloro-tetrazol-1-ylmethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 44

(5R)3-(2-Fluoro-4′-imidazol-1-ylmethyl-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 45

(5S)N-[3-(2-Fluoro-4′-prop-2-ynylaminomethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 46

(5S)N-[3-(4′-Allylaminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 47

(5S)N-[3-(4′-But-3-enylaminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 48

(5S)N-[3-(4′-But-3-ynylaminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 49

(5S)N-[3-(2-Fluoro-4′-pent-4-ynylaminomethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 50

(5S)N-[3-(4′-But-2-ynylaminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 51

(5S)N-{3-[2-Fluoro-4′-(3-fluoro-piperidin-1-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 52

(5S)N-[3-(2-Fluoro-4′-{[3-(3H-[1,2,3]triazol-4-yl)-propylamino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 53

(5S)N-(3-{4′-[(2,2-Difluoro-ethylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 54

(5R)3-(2-Fluoro-4′-prop-2-ynylaminomethyl-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one 55

(5S)N-[3-(2-Fluoro-4′-isoxazolidin-2-ylmethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 56

(5S) N-{3-[4-(6-Cyano-pyridin-3-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 57

(5S)N-(3-{2-Fluoro-4′-[(1-methyl-prop-2-ynylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 58

(5S)N-{3-[3-Fluoro-4-(6-{[(3H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 59

(5S)N-[3-(2-Fluoro-4′-{[(1-methyl-1H-tetrazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 60

(5S)N-[3-(2-Fluoro-4′-{[(2-methyl-2H-tetrazol-5-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 61

(5S)N-(3-{2-Fluoro-4′-[(2-fluoro-allylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 62

(5S)N-(3-{4′-[(2,3Difluoropropylamino)-methyl]-2-fluoro-biphenyl-4-yl}-2-oxo-oxazo1idin-5-ylmethyl)-acetamide 63

(5S)5-{4-[5-(Acety1amino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridine-2-carboxylic acid [2-(3H-imidazol-4-yl)-ethyl]-amide 64

(5S)4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid ([1,2,4]oxadiazol-3-ylmethyl)-amide 65

(5S)4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-carboxylic acid ([1,2,4]thiadiazol-3-ylmethyl)-amide 66

(5S)N-(1-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-ethyl)-2-amino-acetamide 67

(5S)2-(1-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-ethylamino)-acetamide 68

(5S)N-{3-[2-Fluoro-4′-(pyridin-4-ylmethylsulfanyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 69

(5S)N-(3-{2-Fluoro-4′-[(pyridin-4-ylmethyl)-sulfamoyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 70

(S,S)N-(3-{2-Fluoro-4′-[2-(3-fluoro-propylamino)-1-hydroxy-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 71

(5S)N-{3-[2-Fluoro-4′-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 72

(5S)N-{3-[2-Fluoro-4′-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 73

(5S)N-[3-(2-Fluoro-4′-{2-[(tetrahydro-furan-2-ylmethyl)-amino]-thiazol-4-ylmethyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 74

(5S)N-(3-{2-Fluoro-4′-[2-(3-methoxy-benzylamino)-thiazol-4-ylmethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 75

(S,S)N-(3-[4′-(1-Amino-2-imidazol-1-yl-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 76

(5S)5-Aminomethyl-3-(2-fluoro-4′-tetrazol-1-ylmethyl-biphenyl-4-yl)-oxazolidin-2-one 77

(S,S)N-(3-{2-Fluoro-4′-[2-(4-formyl-piperazin-1-yl)-1-hydroxy-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 78

(R,S)N-(3-{2-Fluoro-4′-[1-(4-formyl-piperazin-1-yl)-2-hydroxy-ethyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 79

(S,S)N-{3-[2-Fluoro-4′-(1-hydroxy-2-imidazol-1-yl-ethyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 80

(5S)2,2-Difluoro-N-(3-{2-fluoro-4′-[(3-fluoro-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 81

(5S)2,2-Difluoro-N-[3-fluoro-4′-prop-2-ynylaminomethyl-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

The exemplary compounds in Table 1 can be synthesized by the processdepicted in Scheme A using, for example, the aryl boronic acids and aryliodides listed in Table 2, below.

TABLE 2 M L Y Q Z R³ Product

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 1

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 2

—CH₂— CH B(OH)₂ I —NHAc 3

—CH₂— CH B(OH)₂ I —NHAc 4

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 5

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 6

—CH₂NHCH₂—* CH B(OH)₂ I

7

—CH₂N(CH₃)CH₂— CH B(OH)₂ I —NHAc 8

—CH₂— CH B(OH)₂ I —NHAc 9

—CH₂— CH B(OH)₂ I —NHAc 10 FCH₂CH₂CH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 11NCCH₂CH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 12

—CH₂— CH B(OH)₂ I —NHAc 13 H₂NC(O)CH₂— —NHCH₂—* CH B(OH)₂ I

14 FCH₂CH(OH)CH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 15 FCH₂CH₂CH₂— —NHCH₂—* CHB(OH)₂ I

16 CH₃CH₂— —SO₂NHCH₂—* CH B(OH)₂ I —NHAc 17 CH₃— —NHSO₂CH₂—* CH B(OH)₂ I—NHAc 18

—(CH₂)₃NHC(O)NH—* CH B(OH)₂ I —NHAc 19

—SCH₂CH₂NHCH₂—* CH B(OH)₂ I —NHAc 20

—CH₂SO₂— CH B(OH)₂ I —NHAc 21

—CH₂NHSO₂—* CH B(OH)₂ I —NHAc 22

—SO₂NHCH₂—* CH B(OH)₂ I —NHAc 23

—NHCH₂—* CH B(OH)₂ I —NHAc 24

—S(O)CH₂— CH B(OH)₂ I —NHAc 25 H₂NC(O)CH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 26H₂NCH₂C(O)— —NHCH₂—* CH B(OH)₂ I —NHAc 27 CH₃— —SO₂NHCH₂—* CH B(OH)₂ I—NHAc 28 CH₃— —SO₂NHCH₂—* CF B(OH)₂ I —NHAc 29

—CH₂— CH B(OH)₂ I —NHAc 30

—CH₂S(O)CH₂— CH B(OH)₂ I —NHAc 31

—CH₂— N B(OH)₂ I —NHAc 32

—CH₂— N B(OH)₂ I —NHAc 33

—S(O)CH₂— CH B(OH)₂ I —NHAc 34

—CH₂— CH B(OH)₂ I —NHAc 35

—CH₂— CH B(OH)₂ I —NHAc 36

—CH₂— CH B(OH)₂ I —NHAc 37

—CH₂CH(OH)— CH B(OH)₂ I —NHAc 38 CH₃— —SCH₂CH₂NHCH₂—* CH B(OH)₂ I —NHAc39

—CH₂— N B(OH)₂ I —NHAc 40 NCCH₂—

CH B(OH)₂ I —NHAc 41

—CH₂— N B(OH)₂ I —NHAc 42

—CH₂— CH B(OH)₂ I —NHAc 43

—CH₂— CH B(OH)₂ I

44 HC≡CCH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 45 H₂C═CHCH₂— —NHCH₂—* CH B(OH)₂I —NHAc 46 H₂C═CHCH₂CH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 47 HC≡CCH₂CH₂——NHCH₂—* CH B(OH)₂ I —NHAc 48 HC≡C(CH₂)₃— —NHCH₂—* CH B(OH)₂ I —NHAc 49CH₃C≡CCH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 50

—CH₂— CH B(OH)₂ I —NHAc 51

—(CH₂)₃NHCH₂—* CH B(OH)₂ I —NHAc 52 F₂HCCH₂— —NHCH₂—* CH B(OH)₂ I —NHAc53 HC≡CCH₂— —NHCH₂—* CH B(OH)₂ I

54

—CH₂— CH B(OH)₂ I —NHAc 55 NC— (bond) N B(OH)₂ I —NHAc 56

—NHCH₂—* CH B(OH)₂ I —NHAc 57

—CH₂NHCH₂—* N B(OH)₂ I —NHAc 58

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 59

—CH₂NHCH₂—* CH B(OH)₂ I —NHAc 60 HC═CFCH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 61FH₂CCHFCH₂— —NHCH₂—* CH B(OH)₂ I —NHAc 62

—CH₂CH₂NHC(O)—* N B(OH)₂ I —NHAc 63

—CH₂NHC(O)—* CH B(OH)₂ I —NHAc 64

—CH₂NHC(O)—* CH B(OH)₂ I —NHAc 65 H₂NCH₂C(O)—

CH B(OH)₂ I —NHAc 66 H₂NC(O)CH₂—

CH B(OH)₂ I —NHAc 67

—CH₂S— CH B(OH)₂ I —NHAc 68

—CH₂NHSO₂—* CH B(OH)₂ I —NHAc 69 FCH₂CH₂CH₂— —NHCH₂CH(OH)—* CH B(OH)₂ I—NHAc 70

—CH₂— CH B(OH)₂ I —NHAc 71

—CH₂— CH B(OH)₂ I —NHAc 72

—CH₂— CH B(OH)₂ I —NHAc 73

—CH₂— CH B(OH)₂ I —NHAc 74

CH B(OH)₂ I —NHAc 75

—CH₂— CH B(OH)₂ I —NH₂ 76

—CH₂CH(OH)— CH B(OH)₂ I —NHAc 77

CH B(OH)₂ I —NHAc 78

—CH₂CH(OH)— CH B(OH)₂ I —NHAc 79 FCH₂CH₂CH₂— —NHCH₂—* CH B(OH)₂ I—NHC(O)CHF₂ 80 HC≡CCH₂— —NHCH₂—* CH B(OH)₂ I —NHC(O)CHF₂ 81

Compounds containing L groups having free amines (e.g., compoundsderived from the reagents having L groups marked with * in Table 2)alternatively may be synthesized from the corresponding protected amine(e.g., —CH₂N(BOC)CH₂— or —N(BOC)CH₂—) followed by amine deprotection.

Alternatively, the exemplary compounds in Table 1 can be synthesized bythe process depicted in Scheme B using, for example, the aryl boronicacids and aryl iodides listed in Table 3, below.

TABLE 3 M L Y Z Q R³ Product

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 1

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 2

—CH₂— CH I B(OH)₂ —NHAc 3

—CH₂— CH I B(OH)₂ —NHAc 4

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 5

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 6

—CH₂NHCH₂—* CH I B(OH)₂

7

—CH₂N(CH₃)CH₂— CH I B(OH)₂ —NHAc 8

—CH₂— CH I B(OH)₂ —NHAc 9

—CH₂— CH I B(OH)₂ —NHAc 10 FCH₂CH₂CH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 11NCCH₂CH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 12

—CH₂— CH I B(OH)₂ —NHAc 13 H₂NC(O)CH₂— —NHCH₂—* CH I B(OH)₂

14 FCH₂CH(OH)CH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 15 FCH₂CH₂CH₂— —NHCH₂—* CHI B(OH)₂

16 CH₃CH₂— —SO₂NHCH₂—* CH I B(OH)₂ —NHAc 17 CH₃— —NHSO₂CH₂— CH I B(OH)₂—NHAc 18

—(CH₂)₃NHC(O)NH—* CH I B(OH)₂ —NHAc 19

—SCH₂CH₂NHCH₂—* CH I B(OH)₂ —NHAc 20

—CH₂SO₂— CH I B(OH)₂ —NHAc 21

—CH₂NHSO₂—* CH I B(OH)₂ —NHAc 22

—SO₂NHCH₂—* CH I B(OH)₂ —NHAc 23

—NHCH₂—* CH I B(OH)₂ —NHAc 24

—S(O)CH₂— CH I B(OH)₂ —NHAc 25 H₂NC(O)CH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 26H₂NCH₂C(O)— —NHCH₂—* CH I B(OH)₂ —NHAc 27 CH₃— —SO₂NHCH₂—* CH I B(OH)₂—NHAc 28 CH₃— —SO₂NHCH₂—* CH I B(OH)₂ —NHAc 29

—CH₂— CH I B(OH)₂ —NHAc 30

—CH₂S(O)CH₂— CH I B(OH)₂ —NHAc 31

—CH₂— N I B(OH)₂ —NHAc 32

—CH₂— N I B(OH)₂ —NHAc 33

—S(O)CH₂— CH I B(OH)₂ —NHAc 34

—CH₂— CH I B(OH)₂ —NHAc 35

—CH₂— CH I B(OH)₂ —NHAc 36

—CH₂— CH I B(OH)₂ —NHAc 37

—CH₂CH(OH)— CH I B(OH)₂ —NHAc 38 CH₃— —SCH₂CH₂NHCH₂—* CH I B(OH)₂ —NHAc39

—CH₂— N I B(OH)₂ —NHAc 40 NCCH₂—

CH I B(OH)₂ —NHAc 41

—CH₂— N I B(OH)₂ —NHAc 42

—CH₂— CH I B(OH)₂ —NHAc 43

—CH₂— CH I B(OH)₂

44 HC≡CCH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 45 H₂C═CHCH₂— —NHCH₂—* CH IB(OH)₂ —NHAc 46 H₂C═CHCH₂CH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 47 HC≡CCH₂CH₂——NHCH₂—* CH I B(OH)₂ —NHAc 48 HC≡C(CH₂)₃— —NHCH₂—* CH I B(OH)₂ —NHAc 49CH₃C≡CCH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 50

—CH₂— CH I B(OH)₂ —NHAc 51

—(CH₂)₃NHCH₂—* CH I B(OH)₂ —NHAc 52 F₂HCCH₂— —NHCH₂—* CH I B(OH)₂ —NHAc53 HC≡CCH₂— —NHCH₂—* CH I B(OH)₂

54

—CH₂— CH I B(OH)₂ —NHAc 55 NC— (bond) N I B(OH)₂ —NHAc 56

—NHCH₂—* CH I B(OH)₂ —NHAc 57

—CH₂NHCH₂—* N I B(OH)₂ —NHAc 58

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 59

—CH₂NHCH₂—* CH I B(OH)₂ —NHAc 60 HC═CFCH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 61FH₂CCHFCH₂— —NHCH₂—* CH I B(OH)₂ —NHAc 62

—CH₂CH₂NHC(O)—* N I B(OH)₂ —NHAc 63

—CH₂NHC(O)—* CH I B(OH)₂ —NHAc 64

—CH₂NHC(O)—* CH I B(OH)₂ —NHAc 65 H₂NCH₂C(O)—

CH I B(OH)₂ —NHAc 66 H₂NC(O)CH₂—

CH I B(OH)₂ —NHAc 67

—CH₂S— CH I B(OH)₂ —NHAc 68

—CH₂NHSO₂—* CH I B(OH)₂ —NHAc 69 FCH₂CH₂CH₂— —NHCH₂CH(OH)—* CH I B(OH)₂—NHAc 70

—CH₂— CH I B(OH)₂ —NHAc 71

—CH₂— CH I B(OH)₂ —NHAc 72

—CH₂— CH I B(OH)₂ —NHAc 73

—CH₂— CH I B(OH)₂ —NHAc 74

CH I B(OH)₂ —NHAc 75

—CH₂— CH I B(OH)₂ —NH₂ 76

—CH₂CH(OH)— CH I B(OH)₂ —NHAc 77

CH I B(OH)₂ —NHAc 78

—CH₂CH(OH)— CH I B(OH)₂ —NHAc 79 FCH₂CH₂CH₂— —NHCH₂—* CH I B(OH)₂—NHC(O)CHF₂ 80 HC≡CCH₂— —NHCH₂—* CH I B(OH)₂ —NHC(O)CHF₂ 81

As discussed above, compounds containing L groups having free amines(e.g., compounds derived from the reagents having L groups marked with *in Table 3) alternatively may be synthesized from the correspondingprotected amine (e.g., —CH₂N(BOC)CH₂— or —N(BOC)CH₂—) followed by aminedeprotection.

In addition to the reagents listed in Tables 2 and 3, reagentscontaining other Q groups (e.g., boronic esters, boronic halides, ororganoboranes) and/or reagents containing other Z groups (e.g., otherhalogens or sulfonates) may be used to synthesize the exemplarycompounds in Table 1 according to the processes of the invention.

3. Examples

Embodiments of the present invention are described in the followingexamples, which are meant to illustrate, not to limit, the scope andnature of the invention.

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

Example 1

Scheme 1 depicts the synthesis of compound 11 from aryl iodide 108 andaryl boronic acid 120.

a. Synthesis of Aryl Iodide 108—Method A

Scheme 2 depicts the synthesis of aryl iodide 108 from 3-fluoroanaline101.

A solution of 3-fluoroanaline 101 (18.7 g, 168.3 mmol) intetrahydrofuran (THF, 150 mL) was treated with potassium carbonate(K₂CO₃, 46.45 g, 336.6 mmol, 2.0 equiv) and H₂O (150 mL) before asolution of benzyl chloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 mL,1.1 equiv) in THF (50 mL) was dropwise added into the reaction mixtureat room temperature under N₂. The resulting reaction mixture was stirredat room temperature for 2 h. When TLC showed the reaction was complete,the reaction mixture was treated with H₂O (100 mL) and ethyl acetate(EtOAc, 100 mL). The two layers were separated, and the aqueous layerwas extracted with EtOAc (2×100 mL). The combined organic extracts werewashed with H₂O (2×100 mL) and saturated aqueous sodium chloride (NaCl,100 mL), dried over magnesium sulfate (MgSO₄), and concentrated invacuo. The residue was further dried in vacuo to afford the desired(3-fluoro-phenyl)-carbamic acid benzyl ester 102 (39.2 g, 95% yield) aspale-yellow oil. This product was directly used in subsequent reactionswithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 5.23 (s, 2H,OCH₂Ph), 6.75-6.82 (m, 2H), 7.05 (dd, 1H, J=1.4, 8.2 Hz), 7.22-7.45 (m,6H). C₁₄H₁₂FNO₂, LCMS (EI) m/e 246 (M⁺+H).

A solution of amine 102 (39.2 g, 160.0 mmol) in anhydrous THF (300 mL)was cooled to −78° C. in a dry-ice/acetone bath before a solution ofn-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol,1.1 equiv) was dropwise added under N₂. The resulting reaction mixturewas subsequently stirred at −78° C. for 1 h before a solution of(R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) inanhydrous THF (100 mL) was dropwise added into the reaction mixture at−78° C. under N₂. The resulting reaction mixture was stirred at −78° C.for 30 min before being gradually warmed to room temperature for 12 hunder N₂. When TLC and HPLC/MS showed the reaction was complete, thereaction mixture was quenched with H₂O (200 mL), and the resultingmixture was stirred at room temperature for 1 h before EtOAc (200 mL)was added. The two layers were separated, and the aqueous layer wasextracted with EtOAc (2×100 mL). The combined organic extracts werewashed with H₂O (2×100 mL) and saturated aqueous NaCl (100 mL), driedover MgSO₄, and concentrated in vacuo. White crystals precipitated fromthe concentrated solution when most of the solvent was evaporated. Theresidue was then treated with 20% EtOAc/hexane (100 mL) and theresulting slurry was stirred at room temperature for 30 min. The solidswere collected by filtration and washed with 20% EtOAc/hexane (2×50 mL)to afford the desired(5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one 103 (24.4 g,72.3% yield) as white crystals. This product was directly used insubsequent reactions without further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 1H,J=12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H),7.32-7.56 (m, 3H). C₁₀H₁₀FNO₃, LCMS (EI) m/e 212 (M⁺+H).

A solution of alcohol 103 (10.74 g, 50.9 mmol) in trifluoroacetic acid(TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol,1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showedthe reaction was complete, the reaction mixture was concentrated invacuo. The residue was then treated with H₂O (100 mL) and 20%EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirredat 25° C. for 30 min before being cooled to 0-5° C. for 2 h. The whitesolids were collected by filtration, washed with H₂O (2×25 mL) and 20%EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired(SR)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one 104(15.1 g, 88% yield) as an off-white powder. This product was directlyused in subsequent reactions without further purification. ¹H NMR (300MHz, DMSO-d₆) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H),5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4,11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz). C₁₀H₉FINO₃, LCMS (EI) m/e 338(M⁺+H).

A solution of iodo-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride(CH₂Cl₂, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL,150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at0-5° C. under N₂. The resulting reaction mixture was subsequentlystirred at 0-5° C. for 1 h under N₂. When TLC and HPLC/MS showed thereaction was complete, the reaction mixture was quenched with H₂O (100mL) and CH₂Cl₂ (100 mL). The two layers were separated, and the aqueouslayer was extracted with CH₂Cl₂ (100 mL). The combined organic extractswere washed with H₂O (2×100 mL) and saturated aqueous NaCl (100 mL),dried over MgSO₄, and concentrated in vacuo. The residue was furtherdried in vacuo to afford the desired (5R)-methanesulfonic acid3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 105 (30.71g, 98.9% yield) as an off-white powder. This product was directly usedin subsequent reactions without further purification. C₁₁H₁₁FINO₅S, LCMS(EI) m/e 416 (M⁺+H).

A solution of mesylate 105 (26.38 g, 63.57 mmol) in anhydrousN,N-dimethylformamide (DMF, 120 mL) was treated with solid potassiumphthalimide (12.95 g, 70.0 mmol, 1.1 equiv) at 25° C., and the resultingreaction mixture was warmed to 70° C. for 2 h. When TLC and HPLC showedthe reaction was complete, the reaction mixture was cooled to roomtemperature before being quenched with H₂O (400 mL). The resultingmixture was stirred at room temperature for 10 min before being cooledto 0-5° C. for 1 h. The white precipitate was collected by filtration,washed with water (3×100 mL), and dried in vacuo to afford the desired(5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione106 (27.85 g, 94%) as an off-white powder. This product was directlyused in subsequent reactions without further purification. C₁₈H₁₂FIN₂O₄,LCMS (EI) m/e 467 (M⁺+H).

A solution of phthalimide 106 (23.3 g, 50.0 mmol) in ethanol (EtOH, 150mL) was treated with hydrazine monohydrate (12.52 g, 12.1 mL, 250 mmol,5.0 equiv) at 25° C., and the resulting reaction mixture was warmed toreflux for 2 h. A white precipitate formed as the reaction mixturerefluxed. When TLC and HPLC showed that the reaction was complete, thereaction mixture was cooled to room temperature before being quenchedwith H₂O (100 mL). The aqueous solution was then extracted with CH₂Cl₂(3×200 mL), and the combined organic extracts were washed with H₂O(2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was further dried in vacuo to affordthe desired(5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one 107 (16.0g, 95.2% yield) as a white powder. This product was directly used in thesubsequent reactions without further purification. C₁₀H₁₀FIN₂O₂, LCMS(EI) m/e 337 (M⁺+H).

A suspension of amine 107 (16.0 g, 47.6 mmol) in CH₂Cl₂ (150 mL) wastreated with TEA (9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., andthe resulting reaction mixture was cooled to 0-5° C. before beingtreated with acetic anhydride (Ac₂O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01equiv) at 0-5° C. under N₂. The resulting reaction mixture wassubsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed thereaction was complete, the reaction mixture was quenched with H₂O (100mL). The two layers were separated, and the aqueous layer was extractedwith CH₂Cl₂ (2×50 mL). The combined organic extracts were washed withH₂O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO₄,and concentrated in vacuo. The residue was further dried in vacuo toafford the desired(5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide108 (17.36 g, 96.5% yield) as a white powder. This product was directlyused in subsequent reactions without further purification. ¹H NMR (300MHz, DMSO-d₆) δ 1.63 (s, 3H, NHCOCH₃), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd,1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H,J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH₃).C₁₂H₁₂FIN₂O₃, LCMS (EI) m/e 379 (M⁺+H).

b. Synthesis of Aryl Iodide 108—Method B

Scheme 3 depicts an alternate synthesis of aryl iodide 108 from alcohol103.

A solution of alcohol 103 (6.33 g, 30.0 mmol) in CH₂Cl₂ (60 mL) wastreated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., andthe resulting mixture was cooled to 0-5° C. before MsCl (3.78 g, 2.55mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reactionmixture at 0-5° C. under N₂. The resulting reaction mixture wassubsequently stirred at 0-5° C. for 1 h under N₂. When TLC and HPLC/MSshowed the reaction was complete, the reaction mixture was quenched withH₂O (40 mL) and CH₂Cl₂ (40 mL). The two layers were separated, and theaqueous layer was extracted with CH₂Cl₂ (40 mL). The combined organicextracts were washed with H₂O (2×40 mL) and saturated aqueous NaCl (40mL), dried over MgSO₄, and concentrated in vacuo. The residue wasfurther dried in vacuo to afford the desired (SR)-methanesulfonic acid3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 109 (7.69 g, 88.7%yield) as an off-white powder. This product was directly used insubsequent reactions without further purification. C₁₁H₁₂FNO₅S, LCMS(EI) m/e 290 (M⁺+H).

A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL)was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2equiv) at 25° C., and the resulting reaction mixture was warmed to 70°C. for 4 h. When TLC and HPLC showed the reaction was complete, thereaction mixture was cooled to room temperature before being quenchedwith H₂O (60 mL). The resulting mixture was stirred at room temperaturefor 10 min before being cooled to 0-5° C. for 1 h. The white precipitatewas collected by filtration, washed with water (2×40 mL), and dried invacuo to afford the desired(5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione110 (3.12 g, 91.8% yield) as an off-white powder. This product wasdirectly used in subsequent reactions without further purification.C₁₈H₁₃FN₂O₄, LCMS (EI) m/e 341 (M⁺+H).

A solution of phthalimide 110 (3.0 g, 8.82 mmol) in ethanol (EtOH, 30mL) was treated with hydrazine monohydrate (2.20 g, 2.2 mL, 44.12 mmol,5.0 equiv) at 25° C., and the resulting reaction mixture was warmed toreflux for 2 h. White precipitates formed as the reaction mixture wasrefluxed. When TLC and HPLC showed the reaction was complete, thereaction mixture was cooled to room temperature before being quenchedwith H₂O (20 mL). The aqueous solution was then extracted with CH₂Cl₂(3×40 mL), and the combined organic extracts were washed with H₂O (2×20mL) and saturated aqueous NaCl (20 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was further dried in vacuo to affordthe desired (5S)-5-aminomethyl-3-(3-fluoro-phenyl)-oxazolidin-2-one 111(1.79 g, 96.6% yield) as a white powder. This product was directly usedin the subsequent reactions without further purification. C₁₀H₁₁FN₂O₂,LCMS (EI) m/e 211 (M⁺+H).

A suspension of amine 111 (2.60 g, 12.38 mmol) in CH₂Cl₂ (40 mL) wastreated with TEA (2.50 g, 3.4 mL, 24.76 mmol, 2.0 equiv) at 25° C., andthe resulting reaction mixture was cooled to 0-5° C. before beingtreated with acetic anhydride (Ac₂₀, 1.90 g, 1.75 mL, 18.75 mmol, 1.5equiv) and DMAP (15 mg, 0.12 mmol, 0.01 equiv) at 0-5° C. under N₂. Theresulting reaction mixture was subsequently stirred at 0-5° C. for 2 h.When TLC and HPLC showed the reaction was complete, the reaction mixturewas quenched with H₂O (20 mL). The two layers 3 were separated, and theaqueous layer was then extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were washed with H₂O (2×20 mL) and saturated aqueousNaCl (20 mL), dried over MgSO₄, and concentrated in vacuo. The residuewas further dried in vacuo to afford the desired(5S)—N-[3-(3-fluoro-4-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 112(2.93 g, 94% yield) as a white powder. This product was directly used inthe subsequent reactions without further purification. C₁₂H₁₃FN₂O₃, LCMS(EI) m/e 253 (M⁺+H).

A solution of acetamide 112 (2.3 g, 9.1 mmol) in TFA (20 mL) was treatedwith N-iodosuccinimide (2.3 g, 10.0 mmol, 1.1 equiv) at 25° C., and theresulting reaction mixture was stirred at 25° C. for 2 h. When TLC andHPLC/MS showed the reaction was complete, the reaction mixture wasconcentrated in vacuo. The residue was treated with H₂O (20 mL) and 20%EtOAc/hexane (20 mL) at 25° C., and the resulting mixture was stirred at25° C. for 30 min before being cooled to 0-5° C. for 2 h. The whitesolids were collected by filtration, washed with H₂O (2×20 mL) and 20%EtOAc/hexane (2×20 mL), and dried in vacuo to afford the desired(5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide108 (3.34 g, 96.8% yield) as an off-white powder. This product was foundto be identical with the material obtained from Method A and wasdirectly used in subsequent reactions without further purification.

c. Synthesis of Aryl Boronic Acid 120

Scheme 4 depicts three synthetic routes to aryl boronic acid 115.

i. Synthesis of Amine 113

A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 mL ofCH₂Cl₂ was treated with methanesulfonyl chloride (55 g, 38 mL, 480 mmol,1.2 equiv) at 0° C. The resulting reaction mixture was gradually warmedto room temperature and stirred for 1-2 hours. When ¹H NMR showed thereaction was complete, the reaction mixture was treated with H₂O (100mL), and the two layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (2×100 mL). The combined organic layers were washed with H₂O(3×100 mL) and dried over MgSO₄. The solvent was removed in vacuo toafford the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g,91% yield) as a yellow oil.

A solution of methanesulfonic acid 3-fluoro-propyl ester (34.5 g, 221mmol) in 250 mL of anhydrous DMF was treated with solid potassiumphthalimide (49 g, 265 mmol, 1.2 equiv) at 25° C. The resultingsuspension was warmed to 70-80° C. for 2 hours. When ¹H NMR showed thatthe reaction was complete, the reaction mixture was treated with H₂O(200 mL). The aqueous solution was extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with H₂O (3×100 mL) and dried overMgSO₄. The solvent was removed in vacuo to afford the desired2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 45.5 g theoretical,99.7% yield) as a white powder.

A suspension of 2-(3-fluoro-propyl)-isoindole-1,3-dione (45.4 g, 221mmol) in 400 mL of 95% aqueous ethanol was treated with hydrazinemonohydrate (11.3 g, 11.1 mL, 223 mmol, 1.0 equiv). The solution wasrefluxed for three hours. When ¹H NMR showed the reaction was complete,the reaction mixture was cooled to room temperature before being treatedwith concentrated aqueous HCl (250 mL) to pH 1-2. The whitephthalhydrazide precipitate was collected by filtration and washed with95% aqueous ethanol (4×100 mL). The combined filtrates were thenconcentrated to about 100 mL before 250 mL of H₂O was added. Theinsoluble material was removed by filtration and the filtrates wereconcentrated to dryness in vacuo. The filtrates were recrystallized fromethanol/diethyl ether and dried in vacuo to afford the desired3-fluoro-propylamine monohydrochloride salt 113 (20.83 g, 83.8% yield)as white crystals. This product was used directly in subsequentreactions without further purification. ¹H NMR (DMSO-d₆, 300 MHz) δ1.89-2.07 (m, 2H), 2.52-2.90 (m, 2H), 4.47 (t, 1H, J=5.8 Hz), 4.63 (t,1H, J=5.8 Hz), 8.19 (s, 3H).

ii. Synthesis of Bromide 115

Method A

To a solution of amine 113 (6.0 g, 52.8 mmol, 1.16 equiv) in DMF (200mL) was added 4-bromobenzaldehyde 114 (8.50 g, 45.5 mmol) at roomtemperature. The resulting reaction mixture was then treated with sodiumtriacetoxyborohydride (NaB(OAc)₃H, 16.10 g, 72.0 mmol, 1.6 equiv) atroom temperature and stirred for 2 h. When TLC and HPLC/MS showed thereaction was complete, the reaction mixture was quenched with water (100mL). The resulting aqueous mixture was treated with solid sodiumcarbonate (Na₂CO₃, 99.64 g, 91.0 mmol, 2.0 equiv) and di-tert-butyldicarbonate (BOC₂O, 12.9 g, 59.1 mmol, 1.3 equiv) at room temperature.The mixture was then stirred at room temperature for 1.5 h before beingquenched with water (100 mL). The reaction mixture was then extractedwith EtOAc (3×60 mL). The combined organic extracts were washed with 0.5M aqueous HCl (100 mL) and water (3×100 mL), dried over anhydrous sodiumsulfate (Na₂SO₄) and concentrated in vacuo. The residue was thenpurified by flash column chromatography (3-4% EtOAc/hexane) to affordthe desired (4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butylester 115 (11.38 g, 72% yield) as a colorless oil. C₁₅H₂₁BrFNO₂, HPLC/MS(ESI) m/e 347 (M⁺+H).

Method B

A solution of 4-bromobenzylamine hydrochloride 116 (2.225 g, 10.0 mmol)and potassium carbonate (2.07 g, 15.0 mmol, 1.5 equiv) in THF (20 mL)and water (5 mL) was treated with BOC₂O (2.40 g, 11.0 mmol, 1.1 equiv)at room temperature and stirred for 12 h. When TLC and HPLC/MS showedthe reaction was complete, the reaction mixture was treated with water(10 mL) and EtOAc (40 mL). The two layers were separated, and theaqueous layer was extracted with EtOAc (20 mL). The combined organicextracts were washed with water (2×20 mL) and saturated aqueous NaCl (20mL), dried over MgSO₄, and concentrated in vacuo. The residue wasfurther dried in vacuo to afford the desired (4-bromo-benzyl)-carbamicacid tert-butyl ester 117-(2.60 g, 90.9% yield) as a colorless oil.

To a solution of 117 (286 mg, 1.0 mmol) in anhydrous DMF (3.0 mL) wasadded sodium hydride (NaH, 60% oil dispersion, 48.0 mg, 1.2 mmol, 1.2equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 minbefore 1-bromo-3-fluoropropane 118 (170 mg, 1.2 mmol, 1.2 equiv) wasadded. The reaction mixture was subsequently warmed to 50-60° C. andstirred for 24 hours. The reaction mixture was then quenched with water(10 mL), and the resulting aqueous solution was extracted with EtOAc(2×20 mL). The combined organic extracts were washed with water (10 mL)and saturated aqueous NaCl (10 mL), dried over MgSO₄ and concentrated invacuo. The residue was purified by column chromatography (10-15%EtOAc/hexane gradient elution) to afford the desired(4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115(158 mg, 46% yield) as a colorless oil.

Method C

A solution of 4-bromobenzylbromide 119 (0.30 g, 1.20 mmol) and amine 113(0.272 g, 2.40 mmol, 2.0 equiv) in anhydrous DMF (8.0 mL) was treatedwith diisopropylethylamine (Hunig's base, 2.0 mL) at room temperature.The resulting reaction mixture was warmed to 60° C. for 24 h. When TLCand HPLC showed the reaction was complete, the reaction mixture wascooled to 25° C. before being treated with water (8.0 mL). The resultingaqueous solution was then treated with solid sodium bicarbonate (NaHCO₃,0.30 g, 3.60 mmol, 3.0 equiv) and BOC₂O (0.524 g, 2.40 mmol, 2.0 equiv)at 25° C. and stirred for 24 h. When TLC and HPLC/MS showed the reactionwas complete, the reaction-mixture was treated with water (20 mL) andEtOAc, 20 mL). The two layers were separated, and the aqueous layer wasextracted with EtOAc (2×30 mL). The combined organic extracts werewashed with H₂O (4×10 mL) and saturated aqueous NaCl (10 mL), dried overMgSO₄, and concentrated in vacuo. The residue was purified by columnchromatography (3% EtOAc/hexanes) to afford the desired(4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115(0.24 g, 57.8% yield) as a colorless oil.

iii. Synthesis of Boronic Acid 120

To a solution of bromide 115 (3.0 g, 8.7 mmol) in anhydrous THF (30 mL)at −78° C. was added a 2.5 M solution of n-BuLi in hexane (3.64 mL, 9.1mmol, 1.05 equiv). The resulting reaction mixture was stirred at −78° C.for 1 h before trimethyl borate (B(OMe)₃, 1.2 mL, 10.4 mmol, 1.2 equiv)was added dropwise. The resulting reaction mixture was stirred at −78°C. for j 0.5 h before being gradually warmed to room temperatureovernight. The reaction mixture was poured into water (60 mL), and theaqueous solution was treated with 1.0 N aqueous HCl to pH 4.0. Theaqueous mixture was then extracted with EtOAc (4×30 mL). The combinedorganic extracts were washed with saturated aqueous NaCl (30 mL), driedover anhydrous Na₂SO₄, and concentrated in vacuo to obtain the desired4-(N-tert-butylcarbonyl-3-fluoropropylaminomethyl)phenyl boronic acid120 (2.5 g). This product was directly used in subsequent reactionswithout further purification. C₁₅H₂₃BFNO₄, HPLC/MS (ESI) m/e 312 (M⁺+H).

d. Synthesis of Compound 11

Scheme 5 depicts the synthesis of compound 11 from aryl iodide 108 andaryl boronic acid 120.

A suspension of aryl boronic acid 120 (2.50 g, 8.03 mmol) in a mixtureof toluene (24 mL), EtOH (8 mL), and water (8 mL) was treated with aryliodide 108 (2.53 g, 6.7 mmol, 0.83 equiv) and solid K₂CO₃ (2.80 g, 20.1mmol, 3.0 equiv) at room temperature. The resulting reaction mixture wasdegassed three times under a steady stream of argon beforetetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 387 mg, 0.335mmol, 0.05 equiv) was added. The resulting reaction mixture was degassedthree times under a steady stream of argon before being warmed to refluxfor 8 h. When TLC and HPLC/MS showed the reaction was complete, thereaction mixture was cooled to room temperature before being poured intowater (60 mL) and EtOAc (60 mL). The two layers were separated, and theorganic phase was washed with water (30 mL) and saturated aqueous NaCl(2×30 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theproduct was then recrystallized from EtOAc/hexanes and dried in vacuo toafford the desired(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamicacid tert-butyl ester 121 (1.3 g, 30%) as an off-white powder.

A solution of BOC-amine 121 (15.65 g, 30.3 mmol) in CH₂Cl₂ (30 mL) wastreated with a solution of 4 N hydrogen chloride in 1,4-dioxane (37.5mL, 150.0 mmol, 5.0 equiv) at room temperature and stirred for 12 h.When TLC and HPLC/MS showed that the reaction was complete, the solventswere removed in vacuo. The residue was suspended in a mixture ofacetonitrile (CH₃CN, 200 mL) and methanol (MeOH, 50 mL), and theresulting slurry was stirred at room temperature for 1 h. The solidswere collected by filtration, washed with 20% MeOH/CH₃CN (2×50 mL), anddried in vacuo to afford the desired(5S)—N-(3-{2-fluoro-4′-[(3-fluoro-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamidemono hydrochloride salt 11 (13.0 g, 95.3% yield) as white crystals. ¹HNMR (300 MHz, DMSO-d₆) δ 1.90 (s, 3H, COCH₃), 2.11-2.20 (m, 2H), 3.10(m, 2H), 3.50 (t, 2H, J=5.4 Hz), 3.87 (dd, 1H, J=6.4, 9.2 Hz), 4.24 (t,1H, J=9.1 Hz), 4.27 (s, 2H, ArCH₂), 4.54 (t, 1H, J=5.8 Hz), 4.70 (t, 1H,J=5.8 Hz), 4.83 (m, 1H), 7.50 (dd, 1H, J=2.2, 8.6 Hz), 7.65-7.74 (m, 6H,aromatic-H), 8.37 (t, 1H, J=5.8 Hz, NHCOCH₃), 9.43 (br. s, 2H, RArN⁺H₂).C₂₂H₂₅F₂N₃O₃HCl, LCMS (EI) m/e 418 (M⁺+H).

Example 2

Scheme 6 depicts an alternate synthesis of aryl boronic acid 120, whichis coupled to aryl iodide 108 to yield compound 11.

A solution of 4-formylphenyl boronic acid 122 (10.0 g, 66.69 mmol) inanhydrous DMF (150 mL) was treated with 3-fluoropropylaminehydrochloride salt 113 (8.70 g, 76.70 mmol, 1.15 equiv, prepared asdescribed in Example 1, above) at room temperature. The resultingmixture was treated with NaB(OAc)₃H (28.30 g, 133.39 mmol, 2.0 equiv) atroom temperature and stirred for 3 h. When TLC and HPLC/MS showed thereaction was complete, the reaction mixture was treated with water (150mL), solid Na₂CO₃ (14.14 g, 133.39 mmol, 2.0 equiv), and BOC₂O (22.05 g,100.04 mmol, 1.5 equiv). The resulting reaction mixture was stirred atroom temperature for 3 h. When TLC and HPLC/MS showed the reaction wascomplete, the reaction mixture was poured into water (500 mL) and EtOAc(500 mL). The two layers were separated and the aqueous layer wastreated with a 2 N aqueous HCl (130 mL) to pH 4. The aqueous layer wasthen extracted with EtOAc (160 mL), and the combined organic layers werewashed with water (2×100 mL) and saturated aqueous NaCl (2×100 mL),dried over Na₂SO₄, and concentrated in vacuo. The residue was furtherdried in vacuo to afford the desired4-(N-tert-butylcarbonyl-3-fluoropropylaminomethyl)phenyl boronic acid120 (25.0 g) as a pale-yellow oil. This product was found to beidentical with the material obtained from Example 1 above and wasdirectly used in the subsequent reaction without further purification.

A suspension of aryl boronic acid 120 (25.0 g, 64.30 mmol, 1.45 equiv)in a mixture of toluene (120 mL), EtOH (40 mL), and water (40 mL) wastreated with(5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide108 (16.80 g, 44.44 mmol, prepared as described in Example 1, above) andsolid K₂CO₃ (18.40 g, 133.4 mmol, 3.0 equiv) at room temperature. Theresulting reaction mixture was degassed three times under a steadystream of argon before being treated with Pd(PPh₃)₄ (2.57 g, 2.23 mmol,0.05 equiv). The resulting reaction mixture was degassed three timesunder a steady stream of argon before being warmed to reflux for 8 h.When TLC and HPLC/MS showed the reaction was complete, the reactionmixture was cooled to room temperature before being poured into water(300 mL) and ethyl acetate (EtOAc, 300 mL). The two layers wereseparated, and the organic phase was washed with water (60 mL) andsaturated aqueous NaCl (2×50 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The product was recrystallized from EtOAc/hexanesand dried in vacuo to afford the desired(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamicacid tert-butyl ester 121 (21.2 g, 61.5% yield for three steps) as anoff-white powder.

BOC-protected amine 121 was subsequently treated with 4 N hydrogenchloride in 1,4-dioxane as in Example 1 to afford compound 11. Theproduct obtained from this process was identical by NMR and LCMS to thematerial obtained in Example 1.

Example 3

Scheme 7 depicts the synthesis of compound 11 from aryl bromide 115 andaryl boronic ester 123.

Synthesis of Boronic Ester 123

A suspension of(5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide108 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) inanhydrous 1,4-dioxane (130 mL) was treated with4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol,1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) atroom temperature. The resulting reaction mixture was degassed threetimes under a steady stream of argon before being treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)(Pd(dppf)₂Cl₂, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. Theresulting reaction mixture was degassed three times under a steadystream of argon before being warmed to reflux for 7 h. When HPLC/MSshowed the reaction was complete, the reaction mixture was cooled toroom temperature before being treated with water (100 mL) and ethylacetate (100 mL). The two layers were separated, and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with water (2×50 mL) and saturated aqueous NaCl (50mL), dried over MgSO₄, and concentrated in vacuo. The residual brown oilwas further dried in vacuo to afford the desired(5S)—N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide123 (18.8 g, 94%) as brown solids. This product was directly used insubsequent reactions without further purification. C₁₈H₂₄BFN₂O₅, HPLC/MS(ESI) m/e 379 (M⁺+H).

Synthesis of Compound 11

A solution of boronic ester 123 (1.40 g, 3.7 mmol, 1.3 equiv) and(4-bromo-benzyl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester 115(1.0 g, 2.89 mmol, prepared as described in Example 1, above) in amixture of 1,4-dioxane (21 mL), EtOH (7.0 mL) and H₂O (7.0 mL) wastreated with solid potassium carbonate (1.2 g, 8.7 mmol, 3.0 equiv) atroom temperature. The resulting reaction mixture was degassed threetimes under a steady stream of argon before being treated withPd(dppf)₂Cl₂ (118 mg, 0.144 mmol, 0.05 equiv) at room temperature. Thereaction mixture was degassed three times under a steady stream of argonbefore being warmed to reflux for 2 h. When TLC and HPLC/MS showed thereaction was complete, the reaction mixture was cooled to roomtemperature before being treated with water (60 mL). The aqueoussolution was then extracted with CH₂Cl₂ (3×20 mL), and the combinedorganic extracts were washed with water (2×20 mL) and saturated aqueousNaCl (20 mL), dried over MgSO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography (0-5% MeOH—CH₂Cl₂ gradientelution) to afford the desired(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamicacid tert-butyl ester 121 (1.36 g, 91% yield) as a colorless oil, whichsolidified upon standing at room temperature in vacuo.

BOC-protected amine 121 was subsequently treated with 4 N hydrogenchloride in 1,4-dioxane as in Example 1 to afford compound 11. Theproduct obtained from this process was identical by NMR and LCMS to thematerial obtained in Example 1.

Example 4 Synthesis of Compound 63

Scheme 8 illustrates the synthesis of amide 63. 2,5-Dibromopyridine 124is converted to activated pyridyl ester 125 which is then treated withhistamine 126 to provide amide 127. The Suzuki coupling of 127 andboronate 123 gave the final target amide 63.

Under an argon atmosphere, triethylamine (0.31 mL, 2.25 mmol) was addedto a mixture of 2,5-dibromopyridine 124 (355 mg, 1.5 mmol), palladiumacetate (16.8 mg. 0.075 mmol), Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 43.4 mg, 0.075 mmol)and N-hydroxysuccimide (241.5 mg, 2.1 mmol) in DMSO (2 mL). The solutionwas purged with carbon monoxide for 15 min and stirred under a carbonmonoxide balloon at 80° C. for 16 h. The reaction mixture was thencooled to room temperature, diluted with 20 mL of ethyl acetate andwashed with saturated sodium bicarbonate solution and water. The organicphase was dried over sodium sulfate and evaporated to give crudeproduct. Chromatography on silica gel using hexane:acetone (3:1)provided ester 125 (75 mg; 17%). ¹H NMR (300 MHz, CDCl₃) δ 8.85 (m, 1H),8.06 (m, 2H), 2.90 (s, 4H).

A mixture of active ester 125 (350 mg, 1.17 mmol), histaminedihydrochloride 126 (216 mg, 1.17 mmol) and triethylamine (Et₃N, 0.33mL, 2.34 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature for 1 h.The reaction was washed with brine and dried under vacuum. The crudeproduct was purified by chromatography (15:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O)to afford 127 (280 mg; 81%). LCMS (ESI) m/z 295 (M+H)⁺.

Under an argon atmosphere, a mixture of amide 127 (230 mg, 0.78 mmol),boronate 123 (295 mg, 0.78 mmol), PdCl₂(dppf)₂ (19 mg, 0.023 mmol) andK₂CO₃ (323 mg, 2.34 mmol) in 5 mL of a mixture of dioxane:EtOH:H₂O(3:1:1) were heated at 100° C. for 12 h. The reaction was concentratedand the residue was dissolved in MeOH (2 mL) and CH₂Cl₂ (10 mL).Inorganic salts were removed by filtration. The filtrate wasconcentrated and purified by chromatography(15:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford amide 63 (106 mg; 29%). LCMS(ESI) m/z 467 (M+H)⁺.

Example 5 Synthesis of Compounds 64 and 65

Scheme 9 illustrates the synthesis of amides 64 and 65. Aryl bromides128 and 129 were coupled to boronate 123 to afford 64 and 65respectively.

Synthesis of Compound 64

A mixture of 4-bromobenzoyl chloride (110 mg, 0.5 mmol),1,2,4-oxadiazol-3-yl-methylamine hydrochloride (68 mg, 0.5 mmol), DMF (1drop) and Et₃N (0.33 mL, 2.34 mmol) in CH₂Cl₂ (5 mL) was stirred at roomtemperature for 4 h. The reaction was washed with brine and dried undervacuum to afford crude amide 128. The resultant amide 128 was added to amixture of boronate 123 (189 mg, 0.5 mmol), Pd(dppf)₂C₁₂ (20 mg, 0.025mmol) and K₂CO₃ (207 mg, 1.5 mmol) in 5 mL of dioxane:EtOH:H₂O (3:1:1)under an argon atmosphere. After being heated at 100° C. for 12 h, thereaction was diluted with water and MeOH, and then filtered throughcelite. The filtrate was concentrated to remove organic solvent. Thecrude product was collected by filtration and further purified bychromatography (25:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford compound 246(45 mg; 32% (2 steps)). LCMS (ESI) m/z 452 (M−H)⁺.

Synthesis of Compound 65

A mixture of 4-bromobenzoyl chloride (29 mg, 0.132 mmol),1,2,4-thiadiazol-3-yl-methylamine hydrochloride (20 mg, 0.132 mmol), DMF(1 drop) and Et₃N (27 mg, 0.264 mmol) in THF (4 mL) was stirred at roomtemperature for 2 h. The reaction was concentrated, dissolved in CH₂Cl₂,washed with brine and dried under vacuum to afford crude amide 129. Theresultant amide 129 was added to a mixture of boronate 123 (50 mg, 0.132mmol), PdCl₂(dppf)₂ (6 mg, 0.0066 mmol) and K₂CO₃ (55 mg, 0.396 mmol) in2 mL of dioxane:EtOH:H₂O (3:1:1) under an argon atmosphere. After beingheated at 100° C. for 12 h, the reaction was concentrated, dissolved inEtOAc, washed with brine and dried under vacuum. The crude product waspurified by chromatography on silica gel (25:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O)to afford compound 65 (30 mg; 48% (2 steps)). LCMS (ESI) m/z 470 (M+H)⁺.

Example 6 Synthesis of Compound 66

To a solution of Boc-glycine 130 (1.04 g, 5.88 mmol) and4-bromobenzylethylamine 131 (1.00 g, 4.90 mmol) in CH₂Cl₂ (25 mL) atroom temperature was added Hunig's base (1.30 mL, 7.35 mmol). Themixture was stirred at room temperature for 16 h. The mixture was pouredinto water (40 mL) and sat. NaHCO₃ (3 mL), then extracted with CH₂Cl₂(60 mL), washed with water (100 mL), and dried with Na₂SO₄. The residuewas isolated by column chromatography (50/50/0.1 EtOAc/Hexane/NH₄OH), togive 1.30 g of amide 132 as a white crystalline solid in 69% yield. ¹HNMR (300 MHz, CDCl₃, ppm): δ: 7.37 (d, J=7 Hz, 2H), 7.09 (d, J=7 Hz,1H), 6.50 (s br, 1H), 5.15 (s br, 1H), 5.01-4.95 (m, 1H), 3.69 (d, J=6Hz, 2H), 1.39 (d, J=7 Hz, 3H), 1.37 (s, 9H).

A mixture of amide 132 (143 mg, 0.40 mmol) and boronic ester 123 (168mg, 0.4 mmol), Pd(dppf)₂Cl₂ (16 mg, 0.02 mmol) and K₂CO₃ (221 mg, 1.60mmol) in dioxane (3 mL), EtOH (1 mL) and H₂O (1 mL) was degassed withargon. The mixture was stirred at 90-95° C. for 3 h, then water (10 mL)was added. The mixture was extracted with CH₂Cl₂ (4×30 mL) and driedover Na₂SO₄. The residue was purified by column chromatography(5:100:0.1 MeOH/CH₂Cl₂/NH₄OH) to yield 200 mg Boc-protected product in100% yield. The Boc-protected product (200 mg) taken up in 2 mL CH₂Cl₂and 2 mL TFA and the mixture was stirred at room temperature for 3 hr.The solvent was removed in vacuo and the residue was purified by columnchromatography (15:85:0.1 MeOH/CH₂Cl₂/NH₄OH) to give 168 mg compound 66in 99% yield. ¹H NMR (300 MHz, CDCl₃, ppm, partial): δ: 7.64-7.33 (m,7H), 5.13-5.07 (m, 1H), 4.19 (ddd, J=9, 3, 3 Hz, 1H), 3.87 (ddd, J=9, 7,3 Hz, 1H), 3.77-3.50 (m, 5H), 1.99 (s, 3H), 1.54 (d, J=7 Hz, 3H). LCMS(ESI) m/e 429 (M+H)⁺.

Example 7 Synthesis of Compound 67

Scheme 11 illustrates the synthesis of compound 67.

To a solution of 2-bromoacetamide 133 (827 mg, 5.88 mmol), and4-bromobenzyl-ethylamine 131 (1.00 g, 4.90 mmol) in MeOH (5 mL) andCH₂Cl₂ (5 mL) at room temperature was added Hunig's base (5 mL). Themixture was stirred at 50-60° C. for 16 h, then water (30 mL) was added.The mixture was extracted with CH₂Cl₂ (4×30 mL), dried over Na₂SO₄, andthe solvent was removed in vacuo to provide 1.27 g amide 134 as a whitecrystalline solid in 100% yield. ¹H NMR (300 MHz, CDCl₃, ppm): δ: 7.38(d, J=8 Hz, 2H), 7.09 (d, J=8 Hz, 1H), 6.77 (s br, 1H), 5.69 (s br, 1H),3.67 (q, J=7 Hz, 1H), 3.07 (s, 2H), 1.29 (d, J=7 Hz, 3H).

A mixture of amide 34 (103 mg, 0.40 mmol) and boronic ester 123 (168 mg,0.4 mmol), Pd(dppf)₂Cl₂ (16 mg, 0.02 mmol) and K₂CO₃ (221 mg, 1.60 mmol)in dioxane (3 mL), EtOH (1 mL) and H₂O (1 mL) was degassed with argon.The mixture was stirred at 90-95° C. for 3 h, then water (10 mL) wasadded. The mixture was extracted with CH₂Cl₂ (4×30 mL), dried overNa₂SO₄, and the solvent was removed in vacuo. The residue was purifiedby column chromatography (7:100:0.1 MeOH/CH₂Cl₂/NH₄OH) to yield 85 mgcompound 67 in 50% yield. ¹H NMR (300 MHz, CDCl₃, ppm, partial): δ:7.70-7.30 (m, 7H), 7.09 (s br, 1H), 6.31 (s br, 1H), 5.63 (s br, 1H),4.96-4.92 (m, 1H), 4.22 (t, J=9 Hz, 1H), 3.33 (s, 2H), 2.13 (s, 3H),1.55 (d, J=7 Hz, 3H). LCMS (ESI) m/e 451.2 (M+Na)⁺.

Example 8 Synthesis of Compound 68

Scheme 12 illustrates the synthesis of compound 68.

Synthesis of Bromide 135

A suspension of 4-bromomethylpyridine hydrochloride (1.59 g, 6.3 mmol)in THF (10 mL) was treated dropwise with a solution of potassiumcarbonate (3.33 g, 24.0 mmol) in H₂O (6 mL) at 0-5° C., and theresulting mixture was stirred at 0-5° C. for 10 min before being treateddropwise with a solution of 4-bromo-benzenethiol (1.14 g, 6.0 mmol) inTHF (5.0 mL) at 0-5° C. under N₂. The resulting reaction mixture wassubsequently stirred at 0-5° C. for an additional 20 min. When TLC andLCMS showed that the reaction was complete, the reaction mixture wastreated with water (15 mL) and ethyl acetate (25 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(2×20 mL). The combined organic extracts were washed with water (2×15mL) and saturated aqueous NaCl solution (10 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (5-25% EtOAc-hexane gradient elution) to afford thedesired 4-(4-bromo-phenylsulfanylmethyl)pyridine (1.374 g; 82%) as apale-yellow solid, which was directly used in subsequent reactions.

Synthesis of Compound 68

A solution of boronate 123 (200 mg, 0.53 mmol) and bromide 135 (150 mg,0.53 mmol) in toluene (9 mL) was treated with solid potassium carbonate(220 mg, 1.6 mmol), ethanol (3.0 mL) and H₂O (3.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(16 mg, 0.013 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed to reflux for 2 h. When LCMS showed that the reaction wascomplete, the reaction mixture was cooled to room temperature beforebeing treated with water (10 mL) and ethyl acetate (20 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (2×10 mL). The combined organic extracts were washed with water(2×10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was then purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford compound 68(177 mg; 74%) as a yellow oil, which solidified upon standing at roomtemperature in vacuo. LCMS (ESI) m/z 452 (M+H)⁺.

Example 9 Synthesis of Compound 69

Scheme 13 illustrates the synthesis of compound 69.

4-bromobenzenesulfonyl chloride 136 (2.56 g, 10 mmol) was added to asolution of 4-aminomethylpyridine 137 (1.08 g, 10 mmol) andtriethylamine (2 mL, 14.3 mmol) in THF (20 mL) at 0° C. After stirringat 0° C. for 1 h, 50 mL of water was added. A white solid was collectedby filtration, washing with EtOAc and dried in vacuo to give 3.10 g ofbromide 138 in a yield of 95%.

Bromide 138 (327 mg, 1 mmol), boronate 123 (378 mg, 1 mmol),Pd(dppf)₂Cl₂ (40 mg, 0.05 mmol) and K₂CO₃ (414 mg, 3 mmol) weredissolved 8 mL of a mixture of dioxane:EtOH:H₂O (3:1:1) under argonatmosphere. After heating at 100° C. for 12 hours, the reaction mixturewas added to 20 mL of cool water. The organic solvent was removed invacuo and the crude product was collected by filtration. The crudeproduct was treated with active charcoal and recrystallized in a mixedsolvent system (1:2:2 MeOH/CH₂Cl₂/acetone) to give 155 mg of compound 69in a yield of 31%. MS (ESI): 499.1 (100%, (M+H)⁺).

Example 10 Synthesis of Compound 70

Scheme 14 depicts the synthesis of compound 70.

Synthesis of Epoxide 139

To a solution of 4-bromostyrene (5.00 g, 26.8 mmol) in CH₂Cl₂ (130 mL)was added anhydrous 4-methylmorpholine N-oxide (NMO, 12.90 g, 107.1mmol) and(1S,2S)-(+)-[1,2-(cyclohexanodiamino-N,N′-bis(3,5-di-t-butyl-salicylidene)]manganese(III)chloride (Jacobsen catalyst, 850 mg, 1.34 mmol). The solution was cooledto −78° C., then 3-chloroperoxybenzoic acid (m-CPBA, 7.40 g, 42.8 mmol)was added in four portions every 10 min. The mixture was stirred at −78°C. for 2 h. The reaction was quenched by addition of aqueous Na₂S₂O₃(10.0 g in 30 mL water), then the cooling bath was removed and water (70mL) and 1N NaOH (60 mL) was added. The aqueous phase was extracted withCH₂Cl₂ (3×30 mL), dried with Na₂SO₄, and evaporated. The residue waspurified by flash chromatography (4:100 Et₂O/hexane) to yield 5.20 gepoxide 139 (98% yield).

Synthesis of Compound 70

To a suspension of epoxide 139 (1 mmol) in acetonitrile (3.0 mL) at roomtemperature was added lithium perchloriate (LiClO₄, 1.05 mmol). Afterthe formation of clear solution, benzylamine 140 (1.5 mmol) was added.The mixture was stirred at 80° C. for 4.5 h. The solvent was removed invacuo and the residue was purified by flash column chromatography(3.5:100 MeOH/CH₂Cl₂), to afford 141 (460 mg; 50% yield). LCMS (ESI) m/z307 (4+H)⁺.

A suspension of 141 (1 eq), boronate ester 123 (1 eq), Pd(dppf)₂Cl₂(0.05 eq), and K₂CO₃ (4 eq) in a 3:1:1 mixture of dioxane/EtOH/H₂O wasdegassed by passing a steady stream of argon through the mixture. Themixture was stirred at 80° C. for 3 h. The solvent was removed in vacuoand the residue was purified by flash column chromatography (3:100MeOH/CH₂Cl₂), to yield amine 142 (690 mg; 96% yield). LCMS (ESI) m/z 439(M+H)⁺.

A mixture of amine 142 (80 mg, 0.168 mmol), 3-fluoro-1-bromopropane (47mg, 0.335 mmol) and Hunig's base (117 μL, 0.670 mmol) in DMF (1.5 mL)was stirred at 55-60° C. for 15 h. The solvent was removed in vacuo andresidue was purified by flash column chromatography (2:100 MeOH/CH₂Cl₂),to give 87 mg of the alkylation product (96% yield). LCMS (ESI) m/z 538(M+H)⁺.

To a solution of the alkylation product (80 mg, 0.149 mmol), in EtOH(1.5 mL) at room temperature was added 3N aqueous HCl (120 μL, 0.360mmol), followed by 10% Pd—C (15 mg). The mixture was stirred under theatmosphere of H₂ (1 atm.) for 18 h. The mixture was passed through a padof celite, and the cake was washed with MeOH (3×10 mL). The filtrate wasevaporated to give the HCl salt of compound 70 (57 mg; 79% yield). LCMS(ESI) m/z 448 (M+H)⁺.

Example 11 Synthesis of Compounds 71 and 72

Scheme 15 illustrates the synthesis of compounds 71 and 72.Hydroxyamidine 143 was converted to bromide 144, which was subsequentlycoupled to boronate 123 to afford compound 71. Hydroxyamidine 143 wastransformed to oxadiazole 145, which was coupled to boronate 123 toafford compound 72.

Synthesis of Hydroxyamidine 143

A solution of 4-bromophenylacetonitrile (10 g, 54 mmol) in methanol (100mL) was treated with sodium bicarbonate (2.2 g, 57 mmol) andhydroxylamine hydrochloride (4.0 g, 57 mmol) and refluxed for 1.5 h.Additional sodium bicarbonate (0.21 g, 5.4 mmol) and hydroxylaminehydrochloride (0.38 g, 5.4 mmol) were added, and the reaction mixturewas refluxed for 12 h. The reaction mixture was cooled to 23° C. and thesolvent removed in vacuo to afford hydroxyamidine 143 as a blue powder(4.0 g; 34%).

Synthesis of Compound 71

A solution of hydroxyamidine 143 (0.20 g, 0.91 mmol) in 1,4-dioxane (1mL) was treated with 1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.15 mL, 0.97 mmol) and stirredat 105° C. for 1 h. The reaction mixture was diluted with water andextracted with ethyl acetate. The water layer was treated with 1.0 M HCl(aqueous) until the pH was 2, and then extracted with ethyl acetate. Theorganic layer was dried (Na₂SO₄), and the solvent removed in vacuo toafford bromide 144 as a yellow powder (0.11 g; 49%).

A solution of boronate ester 123 (0.085 g, 0.220 mmol), bromide 144(0.055 g, 0.220 mmol), and potassium carbonate (0.12 g, 0.90 mmol) indioxane (1.4 mL), ethanol (0.46 mL) and water (0.46 mL) was degassed andtreated with Pd(dppf)Cl₂ (6.0 mg, 6.7 μmol), degassed again, and heatedat 80° C. for 1.5 h. The reaction mixture was diluted with CH₂Cl₂ andwater, and the precipitate in the water layer was recovered by vacuumfiltration to afford compound 71 as a grey powder (0.034 g; 36%). LCMS(ESI) m/z 427 (M+H)⁺.

Synthesis of Compound 71

A solution of hydroxyamidine 143 (0.25 g, 1.1 mmol) in pyridine (5 mL)was cooled to 0° C. and treated with a solution of acetic anhydride(0.11 mL, 1.1 mmol) in pyridine (5 mL) and then stirred at 120° C. for1.5 h. The reaction mixture was diluted with ethyl acetate, washed with1M aqueous HCl and saturated aqueous sodium bicarbonate, dried overNa₂SO₄, and the solvent was evaporated in vacuo. The crude product waspurified by flash chromatography to afford bromide 145 as a clear film(0.10 g; 36%).

A solution of boronate ester 123 (0.15 g, 0.40 mmol), bromide 145 (0.10g, 0.40 mmol), and potassium carbonate (0.22 g, 1.6 mmol) in dioxane(2.5 mL), ethanol (0.83 mL) and water (0.83 mL) was degassed and treatedwith Pd(dppf)Cl₂ (10.0 mg, 0.012 mmol), degassed again, and stirred at80° C. for 2 h. The reaction mixture was diluted with CH₂Cl and washedwith water. The water layer was extracted with 2×CH₂Cl₂, dried (Na₂SO₄),and the solvent evaporated in vacuo. The crude product was purified byflash chromatography and preparatory TLC to afford compound 72 as awhite powder (0.054 g; 32%). LCMS (ESI) m/z 425 (M+H)⁺.

Example 12 Synthesis of Compounds 73 and 74

Scheme 16 illustrates the synthesis of compounds 73 and 74. Bromoketone146 was subjected to alkylation with thioureas 147 and 148 to affordthiazoles 149 and 150 respectively. Coupling of 149 and 150 withboronate 123 yielded thiazoles 73 and 74.

Synthesis of Compound 73

Bromoketone 146 (0.29 g, 1.0 mmol) was dissolved in dioxane (10 mL).Thiourea 147 (0.19 g, 1.2 mmol) and potassium carbonate (0.28 g, 2 mmol)were added sequentially and the resulting slurry stirred at 50° C. for 4h. The mixture was cooled to room temperature, diluted with 100 mLCH₂Cl₂, and washed with saturated aqueous NaHCO₃ and brine. The aqueouswashes were back-extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over K₂CO₃, filtered, and concentrated in vacuo toafford bromide 149 as a yellow solid (0.32 g) which was used withoutfurther purification. LCMS (ESI) m/z 353 (M+H)⁺.

The crude bromide 149 (0.20 g, 0.56 mmol), boronate ester 123 (0.25 g,0.66 mmol), and K₂CO₃ (0.14 g, 1.0 mmol) were combined with a 1:1:1mixture of toluene, ethanol and water (2 mL each). The slurry wasdegassed by alternately applying high vacuum to the reaction mixture andflushing with dry argon. The reaction vessel was then sealed and heatedin an 80° C. oil bath for 14 h. The reaction mixture was cooled to roomtemperature, diluted with 100 mL 9:1 CH₂Cl₂/MeOH, and washed with waterand brine (50 mL each). The aqueous washes were back-extracted once with50 mL 9:1 CH₂Cl₂/MeOH. The combined organic extracts were dried overK₂CO₃, filtered, and concentrated in vacuo to afford 0.48 g of a brownsolid. The solid was purified by flash column chromatography (7:3acetone/hexane) to yield compound 73 as an off-white solid (0.17 g, 0.32mmol). LCMS (ESI) m/z 525 M+H)⁺.

Synthesis of Compound 74

Compound 74 was synthesized according to the procedure described abovefor compound 73, using thiourea 148 in place of 147. The couplingreaction of bromide 150 and boronate 123 yielded compound 74 as a whitesolid (0.12 g, 0.21 mmol). LCMS (ESI) m/z 561 (M+H)⁺.

Example 13 Synthesis of Compound 75

Scheme 17 depicts the synthesis of compound 75.D-p-Hydroxyphenyl-glycine 151 was converted to triflate 154, which wassubsequently coupled to boronate 123 to afford alcohol 155. Mesylationof 155, followed by displacement with the anion of imidazole anddeprotection of the BOC group yielded compound 75.

A solution of D-p-hydroxyphenylglycine 151 (23.8 g, 142.3 mmol) andpotassium carbonate (39.3 g, 284.6 mmol) in THF (200 mL) and H₂O (200mL) was treated with BOC₂O (34.14 g, 156.6 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for 2 h. When TLC andLCMS showed that the reaction was complete, the reaction mixture wastreated with ethyl acetate (200 mL) and H₂O (200 mL). The two layerswere separated, and the aqueous solution was extracted with ethylacetate (200 mL). The aqueous layer was then acidified with a 2N aqueousHCl to pH 4 before being extracted with ethyl acetate (2×200 mL). Thecombined organic extracts were then washed with water (2×100 mL) andsaturated aqueous NaCl (100 mL), dried over MgSO₄, and concentrated invacuo. The residual white solids were further dried in vacuo to affordthe crude desired acid 152 (36.5 g; 96%), which was of suitable purityfor use in subsequent reactions.

A solution of acid 152 (4.005 g, 15 mmol) in anhydrous THF (20 mL) wastreated dropwise with a 1 M solution of BH₃-THF in THF (30 mL, 30 mmol)at 0-5° C., and the resulting reaction mixture was stirred at 0-5° C.for an additional 2 h. When TLC and LCMS showed that the reductionreaction was complete, the reaction mixture was treated with water (50mL) and ethyl acetate (50 mL). The mixture was then stirred at 25° C.for 30 min before being separated, and the aqueous layer was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were thenwashed with water (2×20 mL) and saturated aqueous NaCl (20 mL), driedover MgSO₄, and concentrated in vacuo. The residue was then directlypurified by flash column chromatography (0-5% MeOH—CH₂Cl₂ gradientelution) to afford desired alcohol 153 (2.50 g; 66%) as a white powderwhich was of suitable purity for use in subsequent reactions.

A suspension alcohol 153 (670 mg, 2.65 mmol) in CH₂Cl₂ (10 mL) wastreated with N-phenyltrifluoromethane sulfonamide (947 mg, 2.65 mmol)and triethylamine (535.3 mg, 0.74 mL, 5.3 mmol) at 25° C., and theresulting reaction mixture was stirred at 25° C. for an additional 2 h.When TLC and LCMS showed that the reaction was complete, the reactionmixture was quenched with water (10 mL) and CH₂Cl₂ (20 mL). The twolayers were then separated, and the aqueous layer was extracted withCH₂Cl₂ (2×20 mL). The combined organic extracts were then washed withwater (2×10 mL) and saturated aqueous NaCl (10 mL), dried over MgSO₄,and concentrated in vacuo. The residue was then directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford triflate 154 (945 mg; 93%) as a white powder which was ofsuitable purity for use in subsequent reactions.

A solution of boronate 123 (2.162 g, 5.72 mmol) and triflate 154 (1.70g, 4.4 mmol) in toluene (24 mL) was treated with solid potassiumcarbonate (1.82 g, 13.2 mmol), ethanol (8.0 mL) and H₂O (8.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(184 mg, 0.22 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed to reflux for 2 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was cooled to room temperature beforebeing treated with water (20 mL) and ethyl acetate (20 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic extracts were washed with water(2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was then purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford(1-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-yl}-2-hydroxyethyl)carbamicacid tert-butyl ester 155 (1.543 g; 72%) as yellow oil, which solidifiedupon standing at room temperature in vacuo.

A suspension of alcohol 155 (694 mg, 1.43 mmol) in anhydrous CH₂Cl₂ (10mL) was treated with diisopropylethylamine (388 mg, 0.522 mL, 2.85 mmol)and methanesulfonyl chloride (196 mg, 0.132 mL, 1.71 mmol) at 0-5° C.,and the resulting reaction mixture was stirred at 0-5° C. for anadditional 2 h. When TLC and LCMS showed that the reaction was complete,the reaction mixture was quenched with water (10 mL). The two layerswere separated, and the aqueous layer was extracted with CH₂Cl₂ (2×10mL). The combined organic extracts were washed with water (2×10 mL) andsaturated aqueous NaCl (10 mL), dried over MgSO₄, and concentrated invacuo. The residue was then purified by flash column chromatography(0-5% MeOH—CH₂Cl₂ gradient elution) to afford mesylate 156 (647 mg; 80%)as a pale-yellow solid, which was of suitable purity for use insubsequent reactions.

A solution of imidazole (41 mg, 0.6 mmol) in anhydrous THF (3 mL) wastreated with sodium hydride (NaH, 60% oil dispersion, 29 mg, 0.72 mmol)at 0° C., and the resulting mixture was stirred at 0-5° C. for 30 minbefore a solution of mesylate 156 (170 mg, 0.3 mmol) in anhydrous DMF(3.0 mL) was added. The resulting reaction mixture was then stirred at0-5° C. for 30 min before being gradually warmed to room temperature for12 h. When TLC and LCMS showed that the reaction was complete, thesolvents were removed in vacuo, and the residue was directly purified byflash column chromatography (0-5% MeOH—CH₂Cl₂ gradient elution) toafford imidazole 157 (46 mg; 29%) as a yellow solid.

A solution of imidazole 157 (23 mg, 0.043 mmol) in MeOH (1.0 mL) wastreated with 4N HCl in 1,4-dioxane (3.0 mL), and the resulting reactionmixture was stirred at room temperature for 30 min. When TLC and LCMSshowed that the reaction was complete, the solvents were removed invacuo, and the desiredN-{3-[4′-(1-amino-2-imidazol-1-yl-ethyl)-2-fluoro-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}acetamidehydrochloride 75 (18.8 mg; 100%) was obtained as a yellow solid. LCMS(ESI) m/z 438 (M+H)⁺.

Example 14 Synthesis of Compound 76

Scheme 18 depicts the synthesis of compound 76. Iodide 158 was convertedto boronate 159, which was coupled to bromide 160 to afford tetrazole161. Deprotection of 161 afforded compound 76.

Synthesis of Boronate 160

A solution of known5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (2.02 g, 6.0mmol; see U.S. Pat. Nos. 5,523,403 and 5,565,571) and potassiumcarbonate (1.66 g, 12.0 mmol) in THF (20 mL) and H₂O (20 mL) was treatedwith BOC₂O (1.334 g, 6.12 mmol) at 25° C., and the resulting reactionmixture was stirred at 25° C. for 2 h. When TLC and LCMS showed thereaction was complete, the reaction mixture was treated with ethylacetate (20 mL) and H₂O (20 mL). The two layers were separated, and theaqueous solution was extracted with ethyl acetate (20 mL), and thecombined organic extracts were then washed with water (2×10 mL) andsaturated aqueous NaCl (10 mL), dried over MgSO₄, and concentrated invacuo. The residual white solids were further dried in vacuo to affordthe crude, desired iodide 158 (2.40 g; 92%), which was of suitablepurity for use in subsequent reactions.

A solution of iodide 158 (1.11 g, 2.55 mmol) in 1,4-dioxane (25 mL) wastreated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 159 (489 mg, 0.56mL, 3.82 mmol) and triethylamine (772 mg, 1.07 mL, 7.65 mmol) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(107 mg, 0.13 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed to reflux for 6 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was cooled to room temperature beforebeing treated with water (20 mL) and ethyl acetate (20 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (2×20 mL). The combined organic extracts were washed with water(2×20 mL) and saturated aqueous NaCl (20 mL), dried over MgSO₄, andconcentrated in vacuo. The residual brown oil was then purified by flashcolumn chromatography (10-30% EtOAc-hexanes gradient elution) to affordboronate 160 (646 mg; 58%) as a brown oil that solidified upon standingat room temperature in vacuo. The product was of suitable purity for usein subsequent reactions.

Synthesis of Bromide 161

A solution of 4-bromobenzylamine hydrochloride (2.22 g, 10.0 mmol) inacetic acid (30 mL) was treated with triethyl orthoformate (2.964 g,3.29 mL, 20.0 mmol) and sodium azide (NaN₃, 2.30 g, 20.0 mmol) at roomtemperature, and the resulting reaction mixture was subsequently stirredat reflux for 12 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was cooled to room temperature, and thecooled reaction mixture was poured into ice water (100 mL). Theprecipitate was then collected by filtration, washed with water (2×20mL), and dried in vacuo to afford bromide 161 (460 mg; 19%) as a whitesolid which was of suitable purity for use in subsequent reactions.

Synthesis of Compound 76

A solution of boronate 160 (658 mg, 1.5 mmol) and bromide 161 (300 mg,1.25 mmol) in toluene (9.0 mL) was treated with solid potassiumcarbonate (621 mg, 4.5 mmol), ethanol (3.0 mL) and H₂O (3.0 mL) at roomtemperature, and the resulting reaction mixture was degassed three timesunder a steady stream of argon before being treated with Pd(dppf)₂Cl₂(52.3 mg, 0.063 mmol) at room temperature. The reaction mixture was thendegassed three times again under a steady stream of argon before beingwarmed to reflux for 3 h. When TLC and LCMS showed that the reaction wascomplete, the reaction mixture was cooled to room temperature beforebeing treated with water (10 mL) and ethyl acetate (20 mL). The twolayers were separated, and the aqueous layer was extracted with ethylacetate (2×10 mL). The combined organic extracts were washed with water(2×5 mL) and saturated aqueous NaCl (5 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was then purified by flash columnchromatography (0-5% MeOH—CH₂Cl₂ gradient elution) to afford tetrazole162 (357 mg; 61%) as a yellow oil, which solidified upon standing atroom temperature in vacuo.

A solution of tetrazole 162 (350 mg, 0.748 mmol) in EtOAc (5.0 mL) wastreated with 4N HCl in 1,4-dioxane (5.0 mL), and the resulting reactionmixture was stirred at room temperature for 30 min. When TLC and LCMSshowed that the reaction was complete, the solvents were removed invacuo, and the residue was treated with aqueous sodium bicarbonate (10mL) and EtOAc (15 mL). The mixture was stirred at room temperature for30 min before the two layers were separated. The aqueous layer wasextracted with EtOAc (10 mL), and the combined organic extracts werewashed with H₂O (10 mL) and saturated aqueous NaCl (10 mL), dried overMgSO₄, and concentrated in vacuo to afford compound 76 (266 mg; 97%) asa pale-yellow solid. LCMS (ESI) m/z 369 (M+H)⁺.

Example 15 Synthesis of Compounds 77-79

Scheme 19 depicts the synthesis of aryl bromides 163-165 required forthe synthesis of compounds 77-79. Epoxide 139 was treated with 1-formylpiperazine to afford a mixture of bromides 163 and 164. Epoxidering-opening of 139 with imidazole afforded bromide 165. These bromideswere coupled with boronate 123 to afford the target compounds 77-79.

Synthesis of Bromides 163 and 164

To a suspension of epoxide 139 (1 mmol, 1 eq) in acetonitrile (3.0 mL)at room temperature was added LiClO₄ (1.05 mmol, 1.05 eq). After theformation of a clear solution, 1-formyl piperazine (1.5 mmol, 1.5 eq)was added. The mixture was stirred at room temperature for 16 h. Thesolvent was removed in vacuo and the residue was purified by flashchromatography (3:100 MeOH/CH₂Cl₂) to yield 132 mg of bromide 163 and 42mg of bromide 164.

Synthesis of Compound 77

A suspension of bromide 163 (1 eq), boronate 123 (1 eq), PdCl₂(dppf)₂(0.05 eq), and K₂CO₃ (4 eq) in a 3:1:1 mixture of dioxane/EtOH/H₂O wasdegassed by a stream of argon. The mixture was stirred at 80° C. for 3.5h. The solvent was removed in vacuo and the residue was purified byflash chromatography (4:100 MeOH/CH₂Cl₂) to afford 150 mg compound 77.LCMS (ESI) m/z 485 (M+H)⁺.

Synthesis of Compound 78

A suspension of bromide 164 (1 eq), boronate 123 (1 eq), PdCl₂(dppf)₂(0.05 eq), and K₂CO₃ (4 eq) in a 3:1:1 mixture of dioxane/EtOH/H₂O wasdegassed by a stream of argon. The mixture was stirred at 80° C. for 3.5h. The solvent was removed in vacuo and the residue was purified byflash chromatography (5:100 MeOH/CH₂Cl₂) to afford 52 mg compound 78.LCMS (ESI) m/z 485 (M+H)⁺.

Synthesis of Bromide 165

To a suspension of epoxide 139 (1 mmol, 1 eq) in acetonitrile (3.0 mL)at room temperature was added LiClO₄ (1.05 mmol, 1.05 eq). After theformation of a clear solution, imidazole (1.5 mmol, 1.5 eq) was added.The mixture was stirred at 60° C. for 4 h. The solvent was removed invacuo and the residue was purified by flash chromatography (3:100MeOH/CH₂Cl₂) to yield 103 mg of bromide 165.

Synthesis of Compound 79

A suspension of bromide 165 (1 eq), boronate 123 (1 eq), PdCl₂(dppf)₂(0.05 eq), and K₂CO₃ (4 eq) in a 3:1:1 mixture of dioxane/EtOH/H₂O wasdegassed by a stream of argon. The mixture was stirred at 80° C. for 2.5h. The solvent was removed in vacuo and the residue was purified byflash chromatography (10:100 MeOH/CH₂Cl₂) to afford 155 mg compound 79.LCMS (ESI) iii/Z 439 (M+H)⁺.

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A process for preparing a compound having the formula:

the process comprising the steps of: combining a compound of formula(I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, whereinA is phenyl; B is phenyl; Het-CH₂—R³ is

M-L is M-L¹-X-L², wherein X is —NR⁴—; L¹ is C₁₋₆ alkyl; and L² is C₁₋₆alkyl; M is selected from the group consisting of: a) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, b) 3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, c)C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, and f) —CN, wherein any ofa)-e) optionally is substituted with one or more R⁵ groups; Q is aborane having the formula —BY₂, wherein Y, at each occurrence,independently is selected from the group consisting of: a) —OH, b)—OC₁₋₆ alkyl, c) —OC₂₋₆ alkenyl, d) —OC₂₋₆ alkynyl, e) —OC₁₋₁₄saturated, unsaturated, or aromatic carbocycle, f) C₁₋₆ alkyl, g) C₂₋₆alkenyl, h) C₂₋₆ alkynyl, and i) C₁₋₁₄ saturated, unsaturated, oraromatic carbocycle, wherein any of b)-i) optionally is substituted withone or more halogens; alternatively, two Y groups taken togethercomprise a chemical moiety selected from the group consisting of: a)—OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—; alternatively,Q is a BF₃ alkali metal salt or 9-borabicyclo[3.3.1]nonane; Z isselected from the group consisting of: a) I, b) Br, c) Cl, and d)—R⁹SO₃—; R¹, at each occurrence, independently is selected from thegroup consisting of: a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN,h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴,n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)—C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w)—OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa)—C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee)—OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴, hh) —S(O)_(p)R⁴,ii) —SO₂NR⁴R⁴, and jj) R⁴; R², at each occurrence, independently isselected from the group consisting of: a) F, b) Cl, c) Br, d) I, e)—CF₃, f) —OR⁴, g) —CN, h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l)—OC(O)R⁴, m) —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴,q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴,v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)—C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd)—NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴,hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴; R³ is —NR⁴C(O)R⁴; R⁴, ateach occurrence, independently is selected from the group consisting of:a) H, b) —OR⁶, c) an amine protecting group, d) C₁₋₆ alkyl, e) C₂₋₆alkenyl, f) C₂₋₆ alkynyl, g) C₃₋₁₄ saturated, unsaturated, or aromaticcarbocycle, h) 3-14 membered saturated, unsaturated, or aromaticheterocycle comprising one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, i) —C(O)—C₁₋₆ alkyl, j)—C(O)—C₂₋₆ alkenyl, k) —C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, n)—C(O)O—C₁₋₆ alkyl, o) —C(O)O—C₂₋₆ alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q)—C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and r)—C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, wherein any of d)-r) optionally issubstituted with one or more R⁵ groups; R⁵, at each occurrence, isindependently selected from the group consisting of: a) F, b) Cl, c) Br,d) I, e) ═O, f) ═S, g) ═NR⁶, h) ═NOR⁶, i) ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l)—CN, m) —NO₂, n) —NR⁶R⁶, o) —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r)—C(O)NR⁶R⁶, s) —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v)—NR⁶C(O)NR⁶R⁶, w) —C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa)—NR⁶C(S)R⁶, bb) —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶, ee)—C(NR⁶)R⁶, ff) —C(NR⁶)OR⁶, gg) —OC(NR⁶)R⁶, hh) —C(NR⁶)NR⁶R⁶, ii)—NR⁶C(NR⁶)R⁶, jj) —OC(NR⁶)NR⁶R⁶, kk) —NR⁶C(NR⁶)OR⁶, ll) —NR⁶C(NR⁶)NR⁶R⁶,mm) —S(O)_(p)R⁶, nn) —SO₂NR⁶R⁶, and oo) R⁶; R⁶, at each occurrence,independently is selected from the group consisting of: a) H, b) —OR⁸,c) an amine protecting group, d) C₁₋₆ alkyl, e) C₂₋₆ alkenyl, f) C₂₋₆alkynyl, g) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, h)3-14 membered saturated, unsaturated, or aromatic heterocycle comprisingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, i) —C(O)—C₁₋₆ alkyl, j) —C(O)—C₂₋₆ alkenyl, k)—C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromaticcarbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromaticheterocycle comprising one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C₁₋₆ alkyl, o)—C(O)O—C₂₋₆ alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q) —C(O)O—C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 memberedsaturated, unsaturated, or aromatic heterocycle comprising one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, wherein any of d)-r) optionally is substituted with one or moreR⁷ groups; R⁷, at each occurrence, independently is selected from thegroup consisting of: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h)═NOR⁸, i) ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n) —NR⁸R⁸, o)—C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s) —NR⁸C(O)R⁸, t)—OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w) —C(S)R⁸, x) —C(S)OR⁸,y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa) —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc)—NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸, ee) —C(NR⁸)R⁸, ff) —C(NR⁸)OR⁸, gg)—OC(NR⁸)R⁸, hh) —C(NR⁸)NR⁸R⁸, ii) —NR⁸C(NR⁸)R⁸, jj) —OC(NR⁸)NR⁸R⁸, kk)—NR⁸C(NR⁸)OR⁸, ll) —NR⁸C(NR⁸)NR⁸R⁸, mm) —S(O)_(p)R⁸, nn) —SO₂NR⁸R⁸, oo)C₁₋₆ alkyl, pp)C₂₋₆ alkenyl, qq) C₂₋₆ alkynyl, rr) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein any of oo)-ss) optionally is substituted with one or moremoieties selected from the group consisting of R⁸, F, Cl, Br, I, —CF₃,—OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —C(O)NR⁸R⁸,—NR⁸C(O)R⁸, —OC(O)NR⁸R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸,—OC(S)R⁸, —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸,—NR⁸C(S)NR⁸R⁸, —C(NR⁸)R⁸, —C(NR⁸)OR⁸, —OC(NR⁸)R⁸, —C(NR⁸)NR⁸R⁸,—NR⁸C(NR⁸)R⁸, —OC(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)OR⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸,and —S(O)_(p)R⁸; R⁸, at each occurrence, independently is selected fromthe group consisting of: a) H, b) an amine protecting group, c) C₁₋₆alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, g) 3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, h)—C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k)—C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, l)—C(O)-3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated,or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein any of c)-q) optionally is substituted with one or more moietiesselected from the group consisting of F, Cl, Br, I, —CF₃, —OH, —OC₁₋₆alkyl, —SH, —SC₁₋₆ alkyl, —CN, —NO₂, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, —C(O)NH₂, —C(O)NHC₁₋₆ alkyl,—C(O)N(C₁₋₆ alkyl)₂, —NHC(O)C₁₋₆ alkyl, —SO₂NH₂—, —SO₂NHC₁₋₆ alkyl,—SO₂N(C₁₋₆ alkyl)₂, and —S(O)_(p)C₁₋₆ alkyl; R⁹ is selected from thegroup consisting of: a) C₁₋₆ alkyl, b) phenyl, and c) toluoyl; whereinany of a)-c) optionally is substituted with one or more moietiesselected from the group consisting of F, Cl, Br, and I; m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, or 4; and p, at each occurrence, independently is0, 1, or
 2. 2. The process according to claim 1, wherein R⁴ is —CH₃. 3.The process according to claim 1, wherein the compound of formula (II)has the formula:


4. The process according to claim 1, wherein the compound of formula (I)has the formula:


5. The process according to claim 1, wherein M-L is M-CH₂—NR⁴—CH₂—. 6.The process according to claim 5, wherein R⁴ is H.
 7. The processaccording to claim 5, wherein R⁴ is an amine protecting group.
 8. Theprocess according to claim 7, wherein the amine protecting group isselected from the group consisting of: a) benzyl, b)t-butyldimethylsilyl, c) t-butdyldiphenylsilyl, d) t-butyloxycarbonyl,e) p-methoxybenzyl, f) methoxymethyl, g) tosyl, h) trifluoroacetyl, i)trimethylsilyl, j) fluorenyl-methyloxycarbonyl, k)2-trimethylsilyl-ethyoxycarbonyl, l)1-methyl-1-(4-biphenylyl)ethoxycarbonyl, m) allyloxycarbonyl, and n)benzyloxycarbonyl.
 9. The process according to claim 7, furthercomprising the step of removing the amine protecting group.
 10. Theprocess according to claim 5, wherein M comprises a 5-6 memberedsaturated, unsaturated, or aromatic heterocycle comprising one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur.
 11. The process according to claim 10, wherein M is selectedfrom the group consisting of triazole, tetrazole, oxazole, andisoxazole.
 12. The process according to claim 11, wherein M is[1,2,3]triazol-4-yl.
 13. The process according to claim 5, wherein M isselected from the group consisting of: a) C₁₋₆ alkyl, b) C₂₋₆ alkenyl,c) C₂₋₆ alkynyl, and d) —CN, wherein i) any of a)-c) is substituted withone or more moieties selected from the group consisting of F, Cl, Br, I,and —CN; and ii) any of a)-c) optionally is further substituted with oneor more R⁵ groups.
 14. The process according to claim 13, wherein M isC₁₋₆ alkyl substituted with one or more atoms selected from the groupconsisting of F, Cl, Br, and I.
 15. The process according to claim 14,wherein M is —CH₂CH₂CH₂F.
 16. The process according to claim 1, whereinZ is selected from the group consisting of I, trifluoromethanesulfonate,and p-toluenesulfonate.
 17. The process according to claim 16, wherein Zis I.
 18. The process according to claim 1, wherein Q is —B(OH)₂. 19.The process according to claim 1, wherein Q is:


20. The process according to claim 1, wherein Q is —BF₂.KF.
 21. Theprocess according to claim 1, wherein the base is selected from thegroup consisting of alkali metal hydroxides, alkali metal carbonates,alkali metal fluorides, trialkyl amines, and mixtures thereof.
 22. Theprocess according to claim 21, wherein the base is potassium carbonate.23. The process according to claim 21, wherein the ratio of equivalentsof base to equivalents of the compound of formula (I) is about 3:1. 24.The process according to claim 1, wherein the palladium catalyst is aligand coordinated palladium (0) catalyst.
 25. The process according toclaim 24, wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium (0).
 26. The process according to claim 25, wherein the ratioof the equivalents of tetrakis(triphenylphosphine) palladium (0) to theequivalents of the compound of formula (I) is about 1:20.
 27. Theprocess according to claim 1, wherein the solvent comprises an aqueoussolvent.
 28. The process according to claim 27 wherein the solventcomprises a mixture of water, toluene, and ethanol.
 29. The processaccording to claim 28 wherein the solvent comprises a mixture of water,toluene, and ethanol in a ratio of about 1:3:1 by volume.
 30. Theprocess according to claim 1, wherein the process is carried out at atemperature between about 20° C. and about 100° C.
 31. The processaccording to claim 1, wherein the process is carried out at the refluxtemperature of the solvent.
 32. A process for preparing a compoundhaving the formula:

the process comprising the steps of: combining a compound of formula(I):

with a compound of formula (II):

in a solvent in the presence of a base and a palladium catalyst, whereinA is phenyl; B is: phenyl; Het-CH₂—R³ is

M-L is M-L¹-X-L², wherein X is —NR⁴— L¹ is C₁₋₆ alkyl; and L² is C₁₋₆alkyl; M is selected from the group consisting of: a) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, b) 3-14 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, c)C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, and f) —CN, wherein any ofa)-e) optionally is substituted with one or more R⁵ groups; Q is aborane having the formula —BY₂, wherein Y, at each occurrence,independently is selected from the group consisting of: a) —OH, b)—OC₁₋₆ alkyl, c) —OC₂₋₆ alkenyl, d) —OC₂₋₆ alkynyl, e) —OC₁₋₁₄saturated, unsaturated, or aromatic carbocycle, f) C₁₋₆ alkyl, g) C₂₋₆alkenyl, h) C₂₋₆ alkynyl, and i) C₁₋₁₄ saturated, unsaturated, oraromatic carbocycle, wherein any of b)-i) optionally is substituted withone or more halogens; alternatively, two Y groups taken togethercomprise a chemical moiety selected from the group consisting of: a)—OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—; alternatively,Q is a BF₃ alkali metal salt or 9-borabicyclo[3.3.1]nonane; Z isselected from the group consisting of: a) I, b) Br, c) Cl, and d)—R⁹SO₃—; R¹, at each occurrence, independently is selected from thegroup consisting of: a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN,h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴,n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r)—C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w)—OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa)—C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee)—OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴, hh) —S(O)_(p)R⁴,ii) —SO₂NR⁴R⁴, and jj) R⁴; R², at each occurrence, independently isselected from the group consisting of: a) F, b) Cl, c) Br, d) I, e)—CF₃, f) —OR⁴, g) —CN, h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l)—OC(O)R⁴, m) —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴,q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴,v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z)—C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd)—NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴,hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴; R³ is —NR⁴C(O)R⁴; R⁴, ateach occurrence, independently is selected from the group consisting of:a) H, b) —OR⁶, c) an amine protecting group, d) C₁₋₆ alkyl, e) C₂₋₆alkenyl, f) C₂₋₆ alkynyl, g) C₃₋₁₄ saturated, unsaturated, or aromaticcarbocycle, h) 3-14 membered saturated, unsaturated, or aromaticheterocycle comprising one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, i) —C(O)—C₁₋₆ alkyl, j)—C(O)—C₂₋₆ alkenyl, k) —C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, n)—C(O)O—C₁₋₆ alkyl, o) —C(O)O—C₂₋₆ alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q)—C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and r)—C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, wherein any of d)-r) optionally issubstituted with one or more R⁵ groups; R⁵, at each occurrence, isindependently selected from the group consisting of: a) F, b) Cl, c) Br,d) I, e) ═O, f) ═S, g) ═NR⁶, h) ═NOR⁶, i) ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l)—CN, m) —NO₂, n)—NR⁶R⁶, o) —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r)—C(O)NR⁶R⁶, s) —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v)—NR⁶C(O)NR⁶R⁶, w) —C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa)—NR⁶C(S)R⁶, bb) —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶, ee)—C(NR⁶)R⁶, ff) —C(NR⁶)OR⁶, gg) —OC(NR⁶)R⁶, hh) —C(NR⁶)NR⁶R⁶, ii)—NR⁶C(NR⁶)R⁶, jj) —OC(NR⁶)NR⁶R⁶, kk) —NR⁶C(NR⁶)OR⁶, ll) —NR⁶C(NR⁶)NR⁶R⁶,mm) —S(O)_(p)R⁶, nn) —SO₂NR⁶R⁶, and oo) R⁶; R⁶, at each occurrence,independently is selected from the group consisting of: a) H, b) —OR⁸,c) an amine protecting group, d) C₁₋₆ alkyl, e) C₂₋₆ alkenyl, f) C₂₋₆alkynyl, g) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, h)3-14 membered saturated, unsaturated, or aromatic heterocycle comprisingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, i) —C(O)—C₁₋₆ alkyl, j) —C(O)—C₂₋₆ alkenyl, k)—C(O)—C₂₋₆ alkynyl, l) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromaticcarbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromaticheterocycle comprising one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C₁₋₆ alkyl, o)—C(O)O—C₂₋₆ alkenyl, p) —C(O)O—C₂₋₆ alkynyl, q) —C(O)O—C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 memberedsaturated, unsaturated, or aromatic heterocycle comprising one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, wherein any of d)-r) optionally is substituted with one or moreR⁷ groups; R⁷, at each occurrence, independently is selected from thegroup consisting of: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h)═NOR⁸, i) ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n) —NR⁸R⁸, o)—C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s) —NR⁸C(O)R⁸, t)—OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w) —C(S)R⁸, x) —C(S)OR⁸,y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa) —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc)—NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸, ee) —C(NR⁸)R⁸, ff) —C(NR⁸)OR⁸, gg)—OC(NR⁸)R⁸, hh) —C(NR⁸)NR⁸R⁸, ii) —NR⁸C(NR⁸)R⁸, jj) —OC(NR⁸)NR⁸R⁸, kk)—NR⁸C(NR⁸)OR⁸, ll) —NR⁸C(NR⁸)NR⁸R⁸, mm) —S(O)_(p)R⁸, nn) —SO₂NR⁸R⁸, oo)C₁₋₆ alkyl, pp) C₂₋₆ alkenyl, qq) C₂₋₆ alkynyl, rr) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein any of oo)-ss) optionally is substituted with one or moremoieties selected from the group consisting of R⁸, F, Cl, Br, I, —CF₃,—OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —C(O)NR⁸R⁸,—NR⁸C(O)R⁸, —OC(O)NR⁸R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸,—OC(S)R⁸, —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸,—NR⁸C(S)NR⁸R⁸, —C(NR⁸)R⁸, —C(NR⁸)OR⁸, —OC(NR⁸)R⁸, —C(NR⁸)NR⁸R⁸,—NR⁸C(NR⁸)R⁸, —OC(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)OR⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸,and —S(O)_(p)R⁸; R⁸, at each occurrence, independently is selected fromthe group consisting of: a) H, b) an amine protecting group, c) C₁₋₆alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated,unsaturated, or aromatic carbocycle, g) 3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, h)—C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k)—C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, l)—C(O)-3-14 membered saturated, unsaturated, or aromatic heterocyclecomprising one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated,or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated,unsaturated, or aromatic heterocycle comprising one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein any of c)-q) optionally is substituted with one or more moietiesselected from the group consisting of F, Cl, Br, I, —CF₃, —OH, —OC₁₋₆alkyl, —SH, —SC₁₋₆ alkyl, —CN, —NO₂, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆alkyl)₂, —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, —C(O)NH₂, —C(O)NHC₁₋₆ alkyl,—C(O)N(C₁₋₆ alkyl)₂, —NHC(O)C₁₋₆ alkyl, —SO₂NH₂—, —SO₂NHC₁₋₆ alkyl,—SO₂N(C₁₋₆ alkyl)₂, and —S(O)_(p)C₁₋₆ alkyl; R⁹ is selected from thegroup consisting of: a) C₁₋₆ alkyl, b) phenyl, and c) toluoyl; whereinany of a)-c) optionally is substituted with one or more moietiesselected from the group consisting of F, Cl, Br, and I; m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, or 4; and p, at each occurrence, independently is0, 1, or
 2. 33. The process of claim 1, wherein R² is selected from thegroup consisting of F, Cl, Br, and I.
 34. The process of claim 1,wherein R² is F.
 35. The process of claim 1, wherein n is
 1. 36. Theprocess of claim 1, wherein m is
 0. 37. The process of claim 1, whereinthe compound of formula (I) has the formula:


38. The process of claim 1, wherein the compound is


39. The process according to claim 32, wherein M-L is M-CH₂—NR⁴—CH₂—.40. The process according to claim 39, wherein M comprises a 5-6membered saturated, unsaturated, or aromatic heterocycle comprising oneor more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur.
 41. The process according to claim 40, wherein M isselected from the group consisting of triazole, tetrazole, oxazole, andisoxazole.
 42. The process according to claim 41, wherein M is[1,2,3]triazol-4-yl.
 43. The process of claim 32, wherein R² is selectedfrom the group consisting of F, Cl, Br, and I.